CXCR3 antagonists

ABSTRACT

Compounds, compositions and methods that are useful in the treatment of inflammatory and immune conditions and diseases are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of a chemokine receptor. The subject methods are useful for the treatment of inflammatory and immunoregulatory disorders and diseases, such as multiple sclerosis, rheumatoid arthritis and type I diabetes.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisionalapplications Serial No. 60/255,241, filed Dec. 11, 2000 and 60/296,499,filed Jun. 6, 2001, the disclosures of each being incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T cells, eosinophils, basophilsand neutrophils to sites of inflammation (reviewed in Schall, Cytokine,3:165-183 (1991), Schall, et al., Curr. Opin. Immunol., 6:865-873 (1994)and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulatingchemotaxis, other changes can be selectively induced by chemokines inresponsive cells, including changes in cell shape, transient rises inthe concentration of intracellular free calcium ions ([Ca²⁺])_(i),granule exocytosis, integrin upregulation, formation of bioactive lipids(e.g., leukotrienes) and respiratory burst, associated with leukocyteactivation. Thus, the chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation.

[0003] There are four classes of chemokines, CXC (α), CC(β), C(γ), andCX₃C (δ), depending on whether the first two cysteines are separated bya single amino acid (C-X-C), are adjacent (C-C), have a missing cysteinepair (C), or are separated by three amino acids (CXC₃). Theα-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatoryactivity protein (MGSA), and stromal cell derived factor 1 (SDF-1) arechemotactic primarily for neutrophils and lymphocytes, whereasβ-chemokines, such as RANTES, MIP-1α, MIP-1β, monocyte chemotacticprotein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic formacrophages, T-cells, eosinophils and basophils (Deng, et al., Nature,381:661-666 (1996)). The C chemokine lymphotactin shows specificity forlymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)) while theCX₃C chemokine fractalkine shows specificity for lymphocytes andmonocytes (Bazan, et al., Nature, 385:640-644 (1997).

[0004] Chemokines bind specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15:159-165 (1994)) termed“chemokine receptors.” On binding their cognate ligands, chemokinereceptors transduce an intracellular signal through the associatedheterotrimeric G protein, resulting in a rapid increase in intracellularcalcium concentration. There are at least twelve human chemokinereceptors that bind or respond to β-chemokines with the followingcharacteristic pattern: CCR1 (or “CKR-1” or “CC-CKR-1”) MIP-1α, MIP-1β,MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem., 270:22123-22128(1995); Neote, et al., Cell, 72:415-425 (1993)); CCR2A and CCR2B (or“CKR-2A”/“CKR-2A” or “CC-CKR-2A”/“CC-CKR2A”) MCP-1, MCP-3, MCP-4; CCR3(or “CKR-3” or “CC-CKR-3”) eotaxin, RANTES, MCP; (Ponath, et al., J.Exp. Med., 183:2437-2448 (1996)); CCR4 (or “CKR-4” or “CC-CKR-4”) TARC,MDC (Imai, et al., J. Biol. Chem., 273:1764-1768 (1998)); CCR5 (or“CKR-5” or “CC-CKR-5”) MIP-1α, RANTES, MIP-1β (Sanson, et al.,Biochemistry, 35:3362-3367 (1996)); CCR6 MIP-3 alpha (Greaves, et al.,J. Exp. Med., 186:837-844 (1997)); CCR7 MIP-3 beta and 6Ckine (Campbell,et al., J. Cell. Biol., 141:1053-1059(1998)); CCR8 I-309, HHV8 vMIP-I,HHV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al., J. Biol. Chem.,274:21569-21574 (1999)); CCR9 TECK (Zaballos, et al., J. Immunol.,162:5671-5675 (1999)), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al.,J. Biol. Chem., 272:32078-32083 (1997)), and the Duffy blood-groupantigen RANTES, MCP-1 (Chaudhun, et al., J. Biol. Chem., 269:7835-7838(1994)).

[0005] Chemokine receptors, such as CCR1, CCR2, CCR2A, CCR2B, CCR3,CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CX₃CR1, and XCR1 have been implicated as being important mediators ofinflammatory and immunoregulatory disorders and diseases, includingasthma and allergic diseases, as well as autoimmune pathologies such asrheumatoid arthritis and atherosclerosis.

[0006] The CXCR3 chemokine receptor is expressed primarily in Tlymphocytes, and its functional activity can be measured by cytosoliccalcium elevation or chemotaxis. The receptor was previously referred toas GPR9 or CKR-L2. Its chromosomal location is unusual among thechemokine receptors in being localized to Xq13. Ligands that have beenidentified that are selective and of high affinity are the CXCchemokines, IP10, MIG and ITAC.

[0007] The highly selective expression of CXCR3 makes it an ideal targetfor intervention to interrupt inappropriate T cell trafficking. Theclinical indications for such intervention are in T-cell mediatedautoimmune diseases such as multiple sclerosis, rheumatoid arthritis,and type I diabetes. Inappropriate T-cell infiltration also occurs inpsoriasis and other pathogenic skin inflammation conditions, althoughthe diseases may not be true autoimmune disorders. In this regard,up-regulation of IP-10 expression in keratinocytes is a common featurein cutaneous immunopathologies. Inhibition of CXCR3 can be beneficial inreducing rejection in organ transplantation. Ectopic expression of CXCR3in certain tumors, especially subsets of B cell malignancies indicatethat selective inhibitors of CXCR3 will have value in tumorimmunotherapy, particularly attenuation of metastasis.

[0008] In view of the clinical importance of CXCR3, the identificationof compounds that modulate CXCR3 function represents an attractiveavenue into the development of new therapeutic agents. Such compoundsare provided herein.

SUMMARY OF THE INVENTION

[0009] The present invention provides compounds which are useful in thetreatment or prevention of certain inflammatory and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis. The compounds provided herein have the general formula(I):

[0010] wherein X represents a bond, —C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═,—S(O)—, —S(O)₂— or —N═; Z represents a bond, —N═, —O—, —S—, —N(R¹⁷)— or—C(R⁷)═, with the proviso that X and Z are not both a bond; L representsa bond, C(O)—(C₁-C₈)alkylene, (C₁-C₈)alkylene or (C₂-C₈)heteroalkylene;Q represents a bond, (C₁-C₈)alkylene, (C₂-C₈)heteroalkylene, —C(O)—,—OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO— or —CH₂SO₂—, and optionally L andQ can be linked together to form a 5- or 6-membered heterocyclic grouphaving from 1 to 3 heteroatoms. The symbols R¹ and R² independentlyrepresent H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl or heteroaryl, oroptionally are combined to form a 3 to 8-membered ring having from 0 to2 heteroatoms as ring vertices, and optionally R² and L can be linkedtogether to form a 5- or 6-membered heterocyclic group having from 1 to4 heteroatoms. The symbol R³ represents hydroxy, (C₁-Cs)alkoxy, amino,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, (C₂-C₈)heteroalkyl,(C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, amidino, guanidino, ureido,cyano, heteroaryl, —CONR⁹R¹⁰ or —CO₂R¹¹. The symbol R⁴ represents(C₁-C₂₀)alkyl, (C₂-C₂₀)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkylor aryl(C₂-C₆)heteroalkyl. The symbols R⁵ and R⁶ independently representH, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl or aryl, or optionallyR⁵ and R⁶ are combined to form a 3- to 7-membered ring. The symbols R⁷and R⁸ independently represent H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,heteroaryl or aryl. The symbols R⁹, R¹⁰ and R¹¹ each independentlyrepresent H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkylor aryl(C₂-C₈)heteroalkyl.

[0011] Turning next to the ring vertices, Y¹, Y² Y³ and Y⁴, the symbolsY¹ and Y² independently represent —C(R¹²)═, —N═, —O—, —S—, or —N(R¹³)—.The symbol Y³ represents N or C wherein the carbon atom shares a doublebond with either Z or Y⁴; and Y⁴ represents —N(R¹⁴)—, —C(R¹⁴)═, —N═ or—N(R¹⁴)—C(R¹⁵)(R¹⁶)—. In the above groups, the symbol R¹² represents H,halogen, hydroxy, amino, alkylamino, dialkylamino, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally when Y¹ and Y²are both —C(R¹²)═ the two R¹² groups can be combined to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y¹ is—C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² and R⁵ can be combined toform a substituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring. Additionally, the symbol R¹³represents H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkylor aryl(C₂-C₈)heteroalkyl. The symbol R¹⁴ represents (C₁-C₈)alkyl,(C₂-Cg)heteroalkyl, aryl(C₁-C₈)alkyl, aryl(C₂-C₈)heteroalkyl,heteroaryl(C₁-C₈)alkyl, heteroaryl(C₂-C₈)heteroalkyl, heteroaryl andaryl; R¹⁵ and R¹⁶ are independently selected from H, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl; and R¹⁷ is selected from H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl, or optionally when Y² is —C(R¹²)═ or —N(R¹³)—,R¹⁷ can be combined with R¹² or R¹³ to form a substituted orunsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring; with the proviso that when the Y³-containing ringsystem is a quinazolinone or quinolinone ring system, and R⁴—Q— issubstituted or unsubstituted (C₅-C₁₅)alkyl, then R³—L— is other thansubstituted or unsubstituted (C₂-C₈)alkylene or a substituted orunsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″, wherein R′ andR″ are independently selected from the group consisting of hydrogen and(C₁-C₈)alkyl, or optionally are combined with the nitrogen atom to whicheach is attached to form a 5-, 6- or 7-membered ring.

[0012] Unless otherwise indicated, the compounds provided in the aboveformula are meant to include pharmaceutically acceptable salts andprodrugs thereof.

[0013] The present invention also provides pharmaceutical compositionscomprising a compound of formula I and a pharmaceutically acceptableexcipient or carrier.

[0014] The present invention further provides methods for the treatmentor prevention of an inflammatory or immune condition or disorder,comprising administering to a subject in need of such treatment orprevention a therapeutically effective amount of a compound of formulaI.

[0015] The present invention also provides methods for the treatment orprevention of a condition or disorder mediated by the CXCR3 chemokinereceptor, comprising administering to a subject in need of suchtreatment or prevention a therapeutically effective amount of a compoundof formula I.

[0016] The present invention also provides methods for the modulation ofCXCR3, comprising contacting a cell with a compound of formula I.

[0017] The present invention further provides methods for the modulationof CXCR3, comprising contacting a CXCR3 protein with a compound offormula I.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIG. 1 illustrates a general synthesis scheme for racemicsubstituted quinazolinones of the invention.

[0019]FIG. 2 illustrates the generic synthesis of substituted quinolinesof the invention.

[0020]FIG. 3 illustrates the generic synthesis of substitutednaphthalenes of the invention.

[0021]FIG. 4 illustrates the generic synthesis of enantiomericallyenriched substituted quinazolinones and 8-aza-quinazolinones of theinvention.

[0022]FIG. 5 illustrates the generic synthesis of substitutedbenzimidazoles of the invention.

[0023]FIG. 6 illustrates the synthesis of two regioisomeric substitutedthiazoles of the invention.

[0024]FIG. 7 illustrates the generic synthesis of substitutedbenzothiophenes of the invention.

[0025]FIG. 8 illustrates the generic synthesis of substituted imidazolesof the invention.

[0026]FIG. 9 illustrates the generic synthesis of substitutedtriazolinones of the invention.

[0027]FIG. 10 illustrates the generic synthesis of substitutedpurine-6-ones of the invention.

[0028]FIG. 11 illustrates the generic synthesis of regioisomeric (seeFIG. 1) substituted quinazolinones of the invention.

[0029]FIG. 12 illustrates exemplary structures for certain compounds ofthe invention.

[0030]FIG. 13 illustrates a representative synthesis of8-azaquinazolinones of the invention.

[0031] FIGS. 14-18 illustrate synthetic routes for exemplary compoundsof the invention.

[0032]FIG. 19 provides a table showing the CXCR3 antagonist activity forexemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Definitions

[0034] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers.

[0035] The term “alkylene” by itself or as part of another substituentmeans a divalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—, and further includes those groups described below as“heteroalkylene.” Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms, or more.

[0036] The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy)are used in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Similarly, the term dialkylaminorefers to an amino group having two attached alkyl groups that can bethe same or different.

[0037] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, suchas, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. When a prefix such as(C₂-C₈) is used to refer to a heteroalkyl group, the number of carbons(2-8, in this example) is meant to include the heteroatoms as well. Forexample, a C₂-heteroalkyl group is meant to include, for example, —CH₂OH(one carbon atom and one heteroatom replacing a carbon atom) and —CH₂SH.The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied.

[0038] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl”, respectively.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

[0039] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “halo(C₁-C₄)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0040] The term “aryl” means, unless otherwise stated, apolyunsaturated, typically aromatic, hydrocarbon substituent which canbe a single ring or multiple rings (up to three rings) which are fusedtogether or linked covalently. The term “heteroaryl” refers to arylgroups (or rings) that contain from zero to four heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of aryl and heteroarylgroups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below.

[0041] For brevity, the term “aryl” when used in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl andheteroaryl rings as defined above. Thus, the term “arylalkyl” is meantto include those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

[0042] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

[0043] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2′m+1),where m′ is the total number of carbon atoms in such radical. R′, R″ andR′″ each independently refer to H, unsubstituted (C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkyl groups. When R′ and R″are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” in its broadest sense is meant to include groups suchas haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃,—C(O)CF₃, —C(O)CH₂OCH₃, and the like). Preferably, the alkyl groups willhave from 0-3 substituents, more preferably 0, 1, or 2 substituents,unless otherwise specified.

[0044] Similarly, substituents for the aryl and heteroaryl groups arevaried and are selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected from H,(C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.

[0045] Two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—,—O—, —CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —A—(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl.

[0046] As used herein, the term “heteroatom” is meant to include oxygen(O), nitrogen (N), sulfur (S) and silicon (Si).

[0047] The term “pharmaceutically acceptable salts” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic,citric, tartaric, methanesulfonic, and the like. Also included are saltsof amino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, et al. (1977) J. Pharm. Sci. 66:1-19). Certain specific compoundsof the present invention contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

[0048] (1) The terms “treat”, “treating” or “treatment”, as used herein,refer to a method of alleviating or abrogating a disease and/or itsattendant symptoms. The terms “prevent”, “preventing” or “prevention”,as used herein, refer to a method of barring a subject from acquiring adisease.

[0049] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0050] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent drug. They may, for instance, be bioavailableby oral administration whereas the parent drug is not. The prodrug mayalso have improved solubility in pharmacological compositions over theparent drug. A wide variety of prodrug derivatives are known in the art,such as those that rely on hydrolytic cleavage or oxidative activationof the prodrug. An example, without limitation, of a prodrug would be acompound of the present invention which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound of the invention.

[0051] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areintended to be encompassed within the scope of the present invention.Certain compounds of the present invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0052] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the present invention.

[0053] The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Radiolabled compounds areuseful as therapeutic agents, e.g., cancer therapeutic agents, researchreagents, e.g., binding assay reagents, and diagnostic agents, e.g., invivo imaging agents. All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

[0054] Embodiments of the Invention

[0055] The present invention is directed to compounds, compositions andmethods useful in the modulation of chemokine receptor activity,particularly CXCR3. Accordingly, the compounds of the present inventionare those which inhibit at least one function or characteristic of amammalian CXCR3 protein, for example, a human CXCR3 protein. The abilityof a compound to inhibit such a function can be demonstrated in abinding assay (e.g., ligand binding or agonist binding), a signallingassay (e.g., activation of a mammalian G protein, induction of rapid andtransient increase in the concentration of cytosolic free calcium),and/or cellular response function (e.g., stimulation of chemotaxis,exocytosis or inflammatory mediator release by leukocytes).

[0056] Compounds

[0057] The present invention provides compounds that are useful asantagonists of CXCR3, having particular utility for the treatment orprevention of inflammation. The compounds provided herein have thegeneral formula (I):

[0058] wherein X represents a bond, —C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═,—S(O)—, —S(O)₂— or —N═; Z represents a bond, —N═, —O—, —S—, —N(R¹⁷)— or—C(R⁷)═, with the proviso that X and Z are not both a bond; L representsa bond, C(O)—(C₁-Cs)alkylene, (C₁-C₈)alkylene or (C₂-C₈)heteroalkylene;Q represents a bond, (C₁-C₈)alkylene, (C₂-C₈)heteroalkylene, —C(O)—,—OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO—, or —CH₂SO₂—; and optionally Land Q can be linked together to form a 5- or 6-membered heterocyclicgroup having from 1 to 3 heteroatoms. The symbols R¹ and R²independently represent H, (C₁-C₈)alkyl, (C₂-Cg)heteroalkyl, aryl orheteroaryl, or optionally are combined to form a 3 to 8-membered ringhaving from 0 to 2 heteroatoms as ring vertices, and optionally R² canbe linked together with L to form a 5- or 6-membered heterocyclic grouphaving from 1 to 4 heteroatoms. The symbol R³ represents hydroxy,(C₁-C₈)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-Cg)heterocyclyl, (C₁-C₈)acylamino, amidino,guanidino, ureido, cyano, heteroaryl, —CONR⁹R¹⁰ or —CO₂R¹¹. The symbolR⁴ represents (C₁-C₂₀)alkyl, (C₂-C₂₀)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkylor aryl(C₂-C₆)heteroalkyl. The symbols R⁵ and R⁶ independently representH, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl or aryl, or optionallyR⁵ and R⁶ are combined to form a 3- to 7-membered ring. The symbols R⁷and R⁸ independently represent H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,heteroaryl or aryl. The symbols R⁹, R¹⁰ and R¹¹ each independentlyrepresent H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkylor aryl(C₂-C₈)heteroalkyl.

[0059] Turning next to the ring vertices, Y¹, Y², Y³ and Y⁴, the symbolsY¹ and Y² independently represent —C(R¹²)═, —N═, —O—, —S—, or —N(R¹³)—.The symbol Y³ represents N or C wherein the carbon atom shares a doublebond with either Z or Y⁴; and Y⁴ represents —N(R¹⁴)—, —C(R¹⁴)═, —N═ or—N(R¹⁴)—C(R¹⁵)(R¹⁶)—. In the above groups, the symbol R¹² represents H,halogen, hydroxy, amino, alkylamino, dialkylamino, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally when Y¹ and Y²are both —C(R¹²)═ the two R¹² groups can be combined to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y¹ is—C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² and R⁵ can be combined toform a substituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring. Additionally, the symbol R¹³represents H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl, aryl,heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkylor aryl(C₂-C₈)heteroalkyl. The symbol R¹⁴ represents (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl, aryl(C₂-C₈)heteroalkyl,heteroaryl(C₁-C₈)alkyl, heteroaryl(C₂-C₈)heteroalkyl, heteroaryl andaryl; R¹⁵ and R¹⁶ are independently selected from H, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl; and R¹⁷ is selected from H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl, or optionally when Y² is —C(R¹²)═ or —N(R¹³)—,R¹⁷ can be combined with R¹² or R¹³ to form a substituted orunsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring; with the proviso that when the Y³-containing ringsystem is a quinazolinone or quinolinone ring system, and R⁴—Q— issubstituted or unsubstituted (C₅-C₁₅)alkyl, then R³—L— is other thansubstituted or unsubstituted (C₂-C₈)alkylene or a substituted orunsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″, wherein R′ andR″ are independently selected from the group consisting of hydrogen and(C₁-C₈)alkyl, or optionally are combined with the nitrogen atom to whicheach is attached to form a 5-, 6- or 7-membered ring.

[0060] Embodiments represented by the above formula can be appreciatedby replacing the ring system having vertices X, Z, Y¹, Y², Y³ and Y⁴with an appropriate scaffold wherein the attachment points represent theattachment of a R¹⁴ group and the carbon atom that bears the R¹ and R²groups:

[0061] For example, the ring system or “scaffold” is meant to includethe following (including substituted versions thereof) wherein the “A”ring is selected from those embodiments shown as:

[0062] Still other A ring scaffolds are six-membered rings (withoutadditional fused rings) and include:

[0063] In other embodiments, the A ring scaffolds are five-memberedrings (without additional fused rings) and include, for example:

[0064] Typically, the ring substituents (shown as R and R′ groups in theabove five-membered rings, but not shown in the fused ring sets orsix-membered rings above) are designed to provide electronic and/oradditional hydrophobic or hydrophilic character to the molecule to bringthe overall physical characters into conformity with those of the mostpreferred compounds in the series (see Examples).

[0065] Within each of the above groups of embodiments, R¹⁴ is preferablya substituted or unsubstituted aryl group or a substituted orunsubstituted heteroaryl group. More preferably, the aryl or heteroarylgroups will have from 0 to 3 substituents. Still more preferably, 1 or 2substituents. The aryl and heteroaryl groups are preferably selectedfrom phenyl, substituted phenyl, pyridyl, substituted pyridyl,thiazolyl, substituted thiazolyl, pyrimidinyl, substituted pyrimidinyl,thienyl and substituted thienyl. For those embodiments having onesubstituent, the substituent will preferably be in a position para tothe point of attachment to the heterocyclic scaffolding. In the mostpreferred embodiments, the substituents are selected from cyano,halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, CONH₂,methylenedioxy and ethylenedioxy.

[0066] Returning to formula I, in one group of preferred embodiments, Xis —C(O)—. In another group, Z is —N═. In still another group ofpreferred embodiments, Y¹ and Y² are each —C(R²)═, wherein the two R¹²groups are combined to form a fused 6-membered aryl or heteroaryl ring.Particularly preferred, are those embodiments that combine each of thesepreferred groups. Accordingly, in one group of particularly preferredembodiments, X is —C(O)—; Z is —N═; Y³ is C; and Y¹ and Y² are each—C(R¹²)═ wherein the two R¹² groups are combined to form a fused6-membered substituted or unsubstituted aryl or heteroaryl ring.

[0067] In other separate, but preferred embodiments, L is(C₁-C₈)alkylene; Q is —C(O)—, R⁴ is (C₅-C₁₅)alkyl, substituted orunsubstituted phenyl, or biphenyl; R³ is (C₁-C₈)alkoxy,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, (C₂-C₈)heteroalkyl,(C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, cyano, heteroaryl, —CONR⁹R¹⁰ or—CO₂R¹¹; R¹ and R² are each independently H or (C₁-C₄)alkyl; Y³ is C andthe carbon atom shares a double bond with Z; and the Y³-containing ringsystem is selected from quinoline, quinazoline, naphthalene,quinolinone, quinazolinone, triazolinone, pyrimidin-4-one,benzimidazole, thiazole, imidazole, pyridine, pyrazine andbenzodiazepine.

[0068] Still other preferred embodiments can be defined according to theA ring scaffolding. For example, one group of preferred embodiments arethose in which X is —C(O)—; Z is —N═; Y³ is C; and Y¹ and Y² are each—C(R¹²)═. More preferably, the two R¹² groups are combined to form afused 6-membered substituted or unsubstituted aryl or heteroaryl ring.Particularly preferred are those embodiments in which Y⁴ is —N(R¹⁴)— or—C(R¹⁴)═ wherein the R¹⁴ group is a substituted or unsubstituted aryl orheteroaryl. In another group of preferred embodiments, X is —C(R⁵)(R⁶)—;Y⁴ is —N(R¹⁴)—, wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; Y³ is C; Z is —N═; and Y¹ and Y² are each —C(R¹²)═. Inanother group of preferred embodiments, X is —C(R⁵)═; Y⁴ is —C(R¹⁴)═,wherein R¹⁴ is substituted or unsubstituted aryl or heteroaryl; Y³ is C;Z is —N═; and Y¹ and Y² are each —C(R¹²)═. In another group of preferredembodiments, X is a bond; Y⁴ is —N(R¹⁴)—, wherein R¹⁴ is substituted orunsubstituted aryl or heteroaryl; Y³ is C; Z is —N═; and Y¹ and Y² areeach —C(R¹²)═. In another group of preferred embodiments, X is —C(R⁵)═;Y⁴ is —C(R¹⁴)═, wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; Y³ is C; Z is —C(R⁷)═; and Y¹ and Y² are each —C(R¹²)═. Inanother group of preferred embodiments, X is a bond; Z is —N═ or—N(R¹⁷)—; Y⁴ is —C(R¹⁴)═, wherein R¹⁴ is substituted or unsubstitutedaryl or heteroaryl; Y¹ is selected from the group consisting of —O—, —S—and —N(R¹³)—; and Y² is —C(R¹²)═. In this group of embodiments, furtherpreferred are those compounds in which Y¹ is —O— and Z is —N═; compoundsin which Y¹ is —S— and Z is —N═; and compounds in which Y¹ is —N(R¹³)—and Z is —N═. In another group of preferred embodiments, X is —SO₂—; Y⁴is —N(R¹⁴)═, wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; Y³ is C; Z is —N═ or —C(R⁷)═; and Y¹ and Y² are each—C(R¹²)═. In another group of preferred embodiments, X is a bond; Z is—O—, —S— or —N(R¹⁷)—; Y¹ is —N═ or —N(R¹³)—; Y² is —C(R²)═; and Y⁴ is—C(R¹⁴)═ wherein R¹⁴ is substituted or unsubstituted aryl or heteroaryl.Particularly preferred embodiments in this group are those in which Y¹is —N═ and Z is —O—; those in which Y¹ is —N═ and Z is —S—; and those inwhich Z is —N(R¹⁷)—. In another group of preferred embodiments, X is abond; Y¹ is —N(R¹³)— or ═N—; Y² is —C(R¹²)═; Y³ is C; Y⁴ is —C(R¹⁴)═wherein R¹⁴ is substituted or unsubstituted aryl or heteroaryl; and Z is—N(R¹⁷)— or ═N—, with the proviso that Y¹ and Z are not both ═N—. Inanother group of preferred embodiments, X is a bond; Y¹ and Y² are eachindependently —C(R¹²)═; Y³ is C; Y⁴ is —C(R¹⁴)═ wherein R¹⁴ issubstituted or unsubstituted aryl or heteroaryl; and Z is —N(R¹⁷)—, O orS. More preferably, the two R¹² groups are combined to form a fused 5-or 6-membered substituted or unsubstituted aryl or heteroaryl ring. Inanother group of preferred embodiments, X is —C(O)—; Y¹ is _N(R¹³)_; Y²is —N═; Y³ is C; Y⁴ is —N(R¹⁴)— wherein R¹⁴ is substituted orunsubstituted aryl or heteroaryl; and Z is a bond. In another group ofpreferred embodiments, X is —C(O)—; Z is —N(R¹⁷)— wherein R¹⁷ issubstituted or unsubstituted aryl or heteroaryl; Y¹ and Y² are eachindependently —C(R¹²)═; Y³ is C; and Y⁴ is —N═. In another group ofpreferred embodiments, X and Z are —N═, Y¹ and Y² are each independently—C(R¹²)═; Y³ is C; and Y⁴ is —C(R¹⁴)═ wherein R¹⁴ is a substituted orunsubstituted aryl or heteroaryl group. In another group of preferredembodiments, wherein X is —C(O)—; Y⁴ is —N(R¹⁴)—C(R⁵)(R⁶)—; wherein R¹⁴is substituted or unsubstituted aryl or heteroaryl; Y¹ and Y² are eachindependently —C(R¹²)═; Y³ is C; and Z is —N═.

[0069] In each of the above groups of preferred embodiments, R₁ is mostpreferably H.

[0070] In one particularly preferred group of embodiments, the A ring isa fused 6,6 or 6,5-member ring system having the indicated nitrogenvertices (see formula II).

[0071] In formula II, each of A¹, A², A³ and A⁴ is independently C or N.Preferably, no more than two of A¹-A⁴ are N. Additionally, X is —CO—,—CH₂— or a bond; R¹ and R² are each independently H or (C₁-C₄)alkyl; R¹⁴is a substituted or unsubstituted phenyl, pyridyl, thiazolyl, thienyl orpyrimidinyl group; Q is —CO—; L is (C₁-C₈)alkylene; the subscript n isan integer of from 0 to 4; and each R_(a) is independently selected fromhalogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′—C(O)NR″R′″,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, unsubstituted aryl,unsubstituted heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and(unsubstituted aryl)oxy-(C₁-C₄)alkyl. The remaining symbols, R³ and R⁴,have the meanings (and preferred groupings) provided above.

[0072] Still more preferably, the compound has the formula (III):

[0073] wherein A4 is C or N; X is —CO—, —CH₂— or a bond; R¹ and R² areeach independently H or (C₁-C₄)alkyl; R¹⁴ is a substituted orunsubstituted phenyl, pyridyl, thiazolyl, thienyl or pyrimidinyl group;Q is —CO—; L is (C₁-C₈)alkylene; the subscript n is an integer of from 0to 4; and each R_(a) is independently selected from the group consistingof halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, unsubstituted aryl,unsubstituted heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and(unsubstituted aryl)oxy-(C₁-C₄)alkyl. The remaining symbols, R³ and R⁴,have the meanings (and preferred groupings) provided above.

[0074] In one group of preferred embodiments, X is —CO—. In anothergroup of preferred embodiments, X is —CH₂—. In yet another group ofpreferred embodiments, X is a bond.

[0075] Further preferred compounds of formula III are those in which R¹is methyl, ethyl or propyl and R² is hydrogen or methyl. Morepreferably, R¹ and R² are each methyl. Still other preferred compoundsof formula III are those in which R³ is selected from substituted orunsubstituted pyridyl or substituted or unsubstituted imidazolyl. Alsopreferred are those compounds of formula III in which R⁴ is asubstituted or unsubstituted benzyl group, wherein the substituents areselected from halogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano,nitro, and phenyl. A preferred group for L is (C₁-C₄)alkylene. Alsopreferred are those compounds of formula III in which R¹⁴ is selectedfrom substituted phenyl, substituted pyridyl, substituted thiazolyl andsubstituted thienyl, wherein the substituents are selected from cyano,halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, CONH₂,methylenedioxy and ethylenedioxy. Still further preferred are thosecompounds that combine two or more of the preferred groups listed above.

[0076] In particularly preferred embodiments for compounds of formulaIII, X is —CO—; R¹ and R² are each independently selected from the groupconsisting of H, methyl and ethyl; R¹⁴ is selected from the groupconsisting of substituted or unsubstituted phenyl; Q is —CO—; L ismethylene, ethylene or propylene, R³ is selected from the groupconsisting of substituted or unsubstituted pyridyl and substituted orunsubstituted imidazolyl; R⁴ is substituted or unsubstituted benzyl,wherein said substituents are selected from the group consisting ofhalogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano, nitro, and phenyl;and each R_(a) is selected from the group consisting of halogen, —OR′,—OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′,—NR″C(O)R′, —NR′—C(O)NR″R′″, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.

[0077] Exemplary structures within this preferred group of embodimentsare:

[0078] Preparation of the Compounds

[0079] FIGS. 1-18 provide a variety of synthesis routes to the compoundsprovided herein. One of skill in the art will appreciate that thesubstituents (e.g., R′, R″, R′″, R^(iv), etc.) can be altered before,during or after preparation of the heterocyclic scaffolding and thatsuitable adjustments in the exemplary conditions (e.g., temperatures,solvents, etc.) can be made. Additionally, one of skill in the art willrecognize that protecting groups may be necessary for the preparation ofcertain compounds and will be aware of those conditions compatible witha selected protecting group.

[0080] The exemplary methods and the examples described herein areillustrative of the present invention and are not be construed aslimiting the scope thereof.

[0081] Compositions

[0082] In another aspect, the present invention provides pharmaceuticalcompositions for modulating chemokine receptor activity in humans andanimals. The compositions comprise a compound of the present inventionwith a pharmaceutically acceptable carrier or diluent.

[0083] “Modulation” or modulating of chemokine receptor activity, asused herein in its various forms, is intended to encompass antagonism,agonism, partial antagonism and/or partial agonism of the activityassociated with a particular chemokine receptor, preferably the CXCR3receptor. The term “composition” as used herein is intended to encompassa product comprising the specified ingredients (and in the specifiedamounts, if indicated), as well as any product which results, directlyor indirectly, from combination of the specified ingredients in thespecified amounts. By “pharmaceutically acceptable” it is meant thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

[0084] The pharmaceutical compositions for the administration of thecompounds of this invention may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing the active ingredientinto association with the carrier which constitutes one or moreaccessory ingredients. In general, the pharmaceutical compositions areprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

[0085] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108;4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

[0086] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

[0087] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0088] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0089] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0090] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0091] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0092] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[0093] The compounds of the present invention may also be administeredin the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0094] For topical use, creams, ointments, jellies, solutions orsuspensions, etc., containing the compounds of the present invention areemployed. As used herein, topical application is also meant to includethe use of mouth washes and gargles.

[0095] The pharmaceutical composition and method of the presentinvention may further comprise other therapeutically active compounds asnoted herein which are usually applied in the treatment or prevention ofthe above mentioned pathological conditions.

[0096] Methods of Use

[0097] In yet another aspect, the present invention provides methods oftreating CXCR3-mediated conditions or diseases by administering to asubject having such a disease or condition, a therapeutically effectiveamount of a compound or composition of the invention. The “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like.

[0098] As used herein, the phrase “CXCR3-mediated condition or disease”and related phrases and terms refer to a condition characterized byinappropriate, e.g., less than or greater than normal, CXCR3 activity.Inappropriate CXCR3 activity might arise as the result of CXCR3expression in cells which normally do not express CXCR3, increased CXCR3expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases), or, decreased CXCR3 expression (leading to,e.g., certain cancers and angiogenic and vasculogenic-relateddisorders). Inappropriate CXCR3 functional activity might arise as theresult of CXCR3 expression in cells which normally do not express CXCR3,increased CXCR3 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CXCR3 expression.Inappropriate CXCR3 functional activity might also arise as the resultof chemokine secretion by cells which normally do not secrete a CXCchemokine, increased chemokine expression (leading to, e.g.,inflammatory and immunoregulatory disorders and diseases) or decreasedchemokine expression. A CXCR3-mediated condition or disease may becompletely or partially mediated by inappropriate CXCR3 functionalactivity. However, a CXCR3-mediated condition or disease is one in whichmodulation of CXCR3 results in some effect on the underlying conditionor disease (e.g., a CXCR3 antagonist results in some improvement inpatient well-being in at least some patients).

[0099] The term “therapeutically effective amount” means the amount ofthe subject compound that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician or that issufficient to prevent development of or alleviate to some extent one ormore of the symptoms of the disease being treated.

[0100] Diseases and conditions associated with inflammation, infectionand cancer can be treated with the present compounds and compositions.In one group of embodiments, diseases or conditions, including chronicdiseases, of humans or other species can be treated with inhibitors ofCXCR3 function. These diseases or conditions include: (1) inflammatoryor allergic diseases such as systemic anaphylaxis or hypersensitivityresponses, drug allergies, insect sting allergies and food allergies;inflammatory bowel diseases, such as Crohn's disease, ulcerativecolitis, ileitis and enteritis; vaginitis; psoriasis and inflammatorydermatoses such as dermatitis, eczema, atopic dermatitis, allergiccontact dermatitis, urticaria; vasculitis; spondyloarthropathies;scleroderma; asthma and respiratory allergic diseases such as allergicrhinitis, hypersensitivity lung diseases, and the like, (2) autoimmunediseases, such as arthritis (rheumatoid and psoriatic), multiplesclerosis, systemic lupus erythematosus, type I diabetes,glomerulonephritis, and the like, (3) graft rejection (includingallograft rejection and graft-v-host disease) and conditions associatedtherewith, and (4) other diseases in which undesired inflammatoryresponses are to be inhibited, e.g., atherosclerosis, myositis,neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis,meningitis, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis,otitis, chronic obstructive pulmonary disease, sinusitis and Behcet'ssyndrome. In another group of embodiments, diseases or conditions aretreated with agonists of CXCR3 function. Examples of diseases to betreated with CXCR3 agonists include cancers, diseases in whichangiogenesis or neovascularization play a role (neoplastic diseases,retinopathy and macular degeneration), infectious diseases andimmunosuppressive diseases.

[0101] Preferably, the present methods are directed to the treatment orprevention of diseases or conditions selected from neurodegenerativediseases (e.g., Alzheimer's disease), multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis, atherosclerosis, encephalitis,meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis,eczema, uticaria, type I diabetes, asthma, conjunctivitis, otitis,allergic rhinitis, chronic obstructive pulmonary disease, sinusitis,dermatitis, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, Behcet's syndrome, gout, cancer, viral infections (e.g., HIV),bacterial infections, and organ transplant conditions or skin transplantconditions. The term “organ transplant conditions” is meant to includebone marrow transplant conditions and solid organ (e.g., kidney, liver,lung, heart, pancreas or combination thereof) transplant conditions.

[0102] Diseases or conditions that can be treated with the presentcompounds and compositions include diseases commonly associated with (1)inflammatory or allergic diseases, (2) autoimmune diseases, (3) graftrejection and (4) other diseases in which undesired inflammatoryresponses are to be inhibited, as described above. For example,restenosis following a procedure such as balloon angioplasty, iscommonly associated with atherosclerosis and can be treated with thepresent compounds and compositions.

[0103] Depending on the disease to be treated and the subject'scondition, the compounds of the present invention may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

[0104] In the treatment or prevention of conditions which requirechemokine receptor modulation an appropriate dosage level will generallybe about 0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0,400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

[0105] It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

[0106] The compounds of the present invention can be combined with othercompounds having related utilities to treat or prevent inflammatory andimmune disorders and diseases, including asthma and allergic diseases,as well as autoimmune pathologies such as rheumatoid arthritis andatherosclerosis, and those pathologies noted above. In many instances,compositions which include a compound of the invention and analternative or second therapeutic agent have additive or synergisticeffects when administered.

[0107] For example, in the treatment or prevention of inflammation, thepresent compounds may be used in conjunction or combination with anantiinflammatory or analgesic agent such as an opiate agonist, alipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, acyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, aninterleukin inhibitor, such as an interleukin-1 inhibitor, an NMDAantagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal antiinflammatory agent, or acytokine-suppressing antiinflammatory agent, for example with a compoundsuch as acetaminophen, aspirin, codiene, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antiitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextromethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compounds of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) VLA-4 antagonists, (b) steroids such asbeclomethasone, methylprednisolone, betamethasone, prednisone,dexamethasone, and hydrocortisone; (c) immunosuppressants such ascyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506,Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 typeimmunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as .beta.2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®)and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV(PDE-IV); (i) gold compounds such as auranofin and aurothioglucose, 0)inhibitors of phosphodiesterase type IV (PDE-IV); (k) other antagonistsof the chemokine receptors, especially CCR1, CCR2, CCR3, CCR5, CCR6,CCR8 and CCR10; (1) cholesterol lowering agents such as HMG-CoAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvastatin, and other statins), sequestrants(cholestyramine and colestipol), nicotinic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (m) anti-diabetic agents such as insulin, sulfonylureas,biguamides (metformin), α-glucosidase inhibitors (acarbose) andglitazones (troglitazone and pioglitazone); (n) preparations ofinterferon beta (interferon β-1 α, interferon β-1 β); (O) etanercept(Enbrel®), (p) antibody therapies such as orthoclone (OKT3), daclizumab(Zenapax®), infliximab (Remicade®), basiliximab (Simulect®) andanti-CD40 ligand antibodies (e.g., MRP-1); and (q) other compounds suchas 5-aminosalicylic acid and prodrugs thereof, hydroxychloroquine,D-penicillamine, antimetabolites such as azathioprene and6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

[0108] Immunosuppressants within the scope of the present inventionfurther include, but are not limited to, leflunomide, RAD001, ERL080,FTY720, CTLA-4, antibody therapies such as orthoclone (OKT3), daclizumab(Zenapax®) and basiliximab (Simulect®), and antithymocyte globulins suchas thymoglobulins.

[0109] In particularly preferred embodiments, the present methods aredirected to the treatment or prevention of multiple sclerosis using acompound of the invention either alone or in combination with a secondtherapeutic agent selected from betaseron, avonex, azathioprene(Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide. Whenused in combination, the practitioner can administer a combination ofthe therapeutic agents, or administration can be sequential.

[0110] In still other particularly preferred embodiments, the presentmethods are directed to the treatment or prevention of rheumatoidarthritis, wherein the compound of the invention is administered eitheralone or in combination with a second therapeutic agent selected fromthe group consisting of methotrexate, sulfasalazine, hydroxychloroquine,cyclosporine A, D-penicillamine, infliximab (Remicade®), etanercept(Enbrel®), auranofin and aurothioglucose.

[0111] In yet other particularly preferred embodiments, the presentmethods are directed to the treatment or prevention of an organtransplant condition wherein the compound of the invention is used aloneor in combination with a second therapeutic agent selected from thegroup consisting of cyclosporine A, FK-506, rapamycin, mycophenolate,prednisolone, azathioprene, cyclophosphamide and an antilymphocyteglobulin.

[0112] In yet another aspect, the present invention includes methods toevaluate putative specific agonists or antagonists of CXCR3 function.Accordingly, the present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds which modulate the activity of the CXCR3 chemokine receptor.For example, the compounds of this invention are useful for isolatingreceptor mutants, which are excellent screening tools for more potentcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other compounds to theCXCR3 chemokine receptor, e.g., by competitive inhibition. The compoundsof the instant invention are also useful for the evaluation of putativespecific modulators of the CXCR3 chemokine receptor, relative to otherchemokine receptors including CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR8, CCR10, CXCR3 and CXCR4,. One of skill in the art willappreciate that thorough evaluation of specific agonists and antagonistsof the above chemokine receptors has been hampered by the lack ofavailability of non-peptidyl (metabolically resistant) compounds withhigh binding affinity for these receptors. Thus the compounds providedherein are particularly useful in this context. Combinatorial librariesof putative CXCR3 agonists or antagonists can be screened forpharmacological activity in in vitro or in vivo assays. Conventionally,new chemical entities with useful properties are generated byidentifying a chemical compound (called a “lead compound”) with somedesirable property or activity, e.g., CXCR3 chemokine receptormodulation activity, creating variants of the lead compound, andevaluating the property and activity of those variant compounds.However, the current trend is to shorten the time scale for all aspectsof drug discovery. Because of the ability to test large numbers quicklyand efficiently, high throughput screening (HTS) methods are replacingconventional lead compound identification methods.

[0113] In one preferred embodiment, high throughput screening methodsinvolve providing a library containing a large number of potentialtherapeutic compounds (candidate compounds). Such “combinatorialchemical libraries” are then screened in one or more assays to identifythose library members (particular chemical species or subclasses) thatdisplay a desired characteristic activity. The compounds thus identifiedcan serve conventional “lead compounds” or can themselves be used aspotential or actual therapeutics.

[0114] A combinatorial chemical library is a collection of diversechemical compounds generated by either chemical synthesis or biologicalsynthesis by combining a number of chemical “building blocks” such asreagents. For example, a linear combinatorial chemical library, such asa polypeptide (e.g., mutein) library, is formed by combining a set ofchemical building blocks called amino acids in every possible way for agiven compound length (i.e., the number of amino acids in a polypeptidecompound). Millions of chemical compounds can be synthesized throughsuch combinatorial mixing of chemical building blocks (Gallop et. al.(1994) J. Med. Chem. 37(9):1233-1251).

[0115] Preparation and screening of combinatorial chemical libraries iswell known to those of skill in the art. Such combinatorial chemicallibraries include, but are not limited to, peptide libraries (see, e.g.,U.S. Pat. No. 5,010,175, Furka (1991) Int. J. Pept. Prot. Res.37:487-493, Houghton et. al. (1991) Nature 354: 84-88), peptoidlibraries (PCT Publication No WO 91/19735), encoded peptide libraries(PCT Publication WO 93/20242), random bio-oligomer libraries (PCTPublication WO 92/00091), benzodiazepine libraries (U.S. Pat. No.5,288,514), libraries of diversomers, such as hydantoins,benzodiazepines and dipeptides (Hobbs et. al. (1993) Proc. Nat. Acad.Sci. USA 90:6909-6913), vinylogous polypeptide libraries (Hagihara etal. (1992) J. Amer. Chem. Soc. 114:6568), libraries of nonpeptidylpeptidomimetics with a Beta-D-Glucose scaffolding (Hirscbmann et al.(1992) J. Amer. Chem. Soc. 114:9217-9218), analogous organic synthesesof small compound libraries (Chen et. al. (1994) J. Am. Chem. Soc.116:2661), oligocarbamate libraries (Cho et al. (1993) Science 261:1303)and/or peptidyl phosphonate libraries (Campbell et al. (1994) J. Org.Chem. 59:658). See, generally, Gordon et al. (1994) J. Med. Chem.37:1385-1401, nucleic acid libraries (see, e.g., Stratagene Corp.),peptide nucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083),antibody libraries (see, e.g., Vaughn et. al. (11996) NatureBiotechnology 14(3):309-314), and PCT/US96/10287), carbohydratelibraries (see, e.g., Liang et al. (11996) Science 274:1520-1522, andU.S. Pat. No. 5,593,853), and small organic molecule libraries (see,e.g., benzodiazepines, Baum (1993) C&EN January 18, page 33;isoprenoids, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos.5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. No. 5,506,337;benzodiazepines, U.S. Pat. No. 5,288,514; and the like).

[0116] Devices for the preparation of combinatorial libraries arecommercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech,Louisville Ky.; Symphony, Rainin, Woburn Mass.; 433A Applied Biosystems,Foster City Calif.; 9050 Plus, Millipore, Bedford, Mass.).

[0117] A number of well known robotic systems have also been developedfor solution phase chemistries. These systems includes automatedworkstations like the automated synthesis apparatus developed by TakedaChemical Industries, LTD. (Osaka, Japan) and many robotic systemsutilizing robotic arms (Zymate II, Zymark Corporation, Hopkinton Mass.;Orca, Hewlett-Packard, Palo Alto Calif.), which mimic the manualsynthetic operations performed by a chemist. Any of the above devicesare suitable for use with the present invention. The nature andimplementation of modifications to these devices (if any) so that theycan operate as discussed herein will be apparent to persons skilled inthe relevant art. In addition, numerous combinatorial libraries arethemselves commercially available (see e.g., ComGenex, Princeton N.J.;Asinex, Moscow, Russia; Tripos, Inc., St. Louis Mo.; ChemStar, Ltd,Moscow, Russia; 3D Pharmaceuticals, Exton Pa.; Martek Biosciences,Columbia Md.; etc.).

[0118] High throughput assays for the presence, absence, quantification,or other properties of particular compounds may be used to test acombinatorial library that contains a large number of potentialtherapeutic compounds (potential modulator compounds). The assays aretypically designed to screen large chemical libraries by automating theassay steps and providing compounds from any convenient source toassays, which are typically run in parallel (e.g., in microtiter formatson microtiter plates in robotic assays). Preferred assays detectenhancement or inhibition of CXCR3 receptor function.

[0119] High throughput screening systems are commercially available (seee.g., Zymark Corp., Hopkinton Mass.; Air Technical Industries, MentorOhio; Beckman Instruments, Inc., Fullerton CA; Precision Systems, Inc.,Natick Mass.; etc.). These systems typically automate entire procedures,including all sample and reagent pipetting, liquid dispensing, timedincubations, and final readings of the microplate in detector(s)appropriate for the assay. These configurable systems provide highthroughput and rapid start up as well as a high degree of flexibilityand customization. The manufacturers of such systems provide detailedprotocols for various high throughput systems. Thus, for example, ZymarkCorp. provides technical bulletins describing screening systems fordetecting the modulation of gene transcription, ligand binding, and thelike.

EXAMPLES

[0120] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMRspectra were recorded on a Varian Gemini 400 MHz NMR spectrometer.Significant peaks are tabulated in the order: number of protons,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet) and coupling constant(s) in Hertz (Hz).Electron Ionization (EI) mass spectra were recorded on a Hewlett Packard5989A mass spectrometer. Mass spectrometry results are reported as theratio of mass over charge, followed by the relative abundance of eachion (in parentheses). In tables, a single m/e value is reported for theM+H (or, as noted, M−H) ion containing the most common atomic isotopes.Isotope patterns correspond to the expected formula in all cases.Electrospray ionization (ESI) mass spectrometry analysis was conductedon a Hewlett-Packard 1100 MSD electrospray mass spectrometer using theHP1 100 HPLC for sample delivery. Normally the analyte was dissolved inmethanol at 0.1 mg/mL and 1 microliter was infused with the deliverysolvent into the mass spectrometer, which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, using1:1 acetonitrile/water with 1% acetic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery solvent.

Example 1 Synthesis of Compound 1.01

[0121] The synthesis of compound 1.01 in six steps from commerciallyavailable anthranilic acid provides an example of 3H-quinazolin-4-onesynthesis by Method 1. Scheme 1 provides an overview of the syntheticroute, for which the experimental details follow.

[0122] 2-Propionylamino-benzoic Acid (II).

[0123] To a room temperature solution of 50.22 g anthranilic acid (I)(370 mmol, 1.00 equiv) dissolved in 200 mL dry DMF was added 35.0 mLpropionyl chloride (400 mmol, 1.10 equiv) dropwise by addition funnelover 1.5 h. The addition rate was slow enough to maintain internaltemperature of the reaction below 38° C. Upon completed addition of theacid chloride, the heterogeneous reaction mixture was stirred for 2.5 hat ambient temperature and then poured into 1600 mL water. The resultingwater/DMF mixture, with white precipitate, was stirred vigorously atambient temperature for one h, after which time the solid was collectedby vacuum filtration, rinsing the solid with cold water (2×100 mL). Theproduct was dried in vacuo over phosphorous pentoxide overnightaffording 48.04 g of a white solid. m.p. 120.1° C. ¹H NMR (CDCl₃) δ1.30(t, 3H, J=7.4 Hz), 2.52 (q, 2H, J=7.4 Hz), 7.12 (t, 1H, J=7.2 Hz), 7.60(t, 1H, J=7.1 Hz), 8.13 (d, 1H, J=6.3 Hz), 8.76 (d, 1H, J=7.8 Hz) ppm.MS (ESI⁻) 192.1 [M−H]⁻.

[0124] 2-Ethyl-benzo[d][1,3]oxazin-4-one (III).

[0125] A mixture of 46.66 g 2-propionylamino-benzoic acid (II) (240mmol, 1.00 equiv) suspended in 180 mL acetic anhydride was heated toreflux (external temperature 170° to 180° C., oil bath) in a reactionvessel fitted with a distillation head. Acetic acid was distilled fromthe reaction (b.p. 116 to 118° C.) over 1.5 to 2 h, after which timeacetic anhydride began to distill (b.p. 136 to 138° C.). The reactionwas equilibrated to room temperature and acetic anhydride removed byvacuum distillation; a light yellow solid resulted from concentration ofthe reaction solution. The solid was triturated with hexane, collectedby filtration (3×100 mL volumes of hexane), and then dried in vacuo overphosphorous pentoxide to afford 33.26 g of a light yellow solid. m.p.83.9° C. ¹H NMR (CDCl₃) δ1.37 (t, 3H, J=7.6 Hz), 2.73 (q, 2H, J=7.6 Hz),7.49 (t, 1H, J₁=1.1 Hz, J₂=7.6 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.78 (t, 1H,J₁=1.5 Hz, J₂=7.2 Hz), 8.18 (d, 1H, J=7.0 Hz) ppm. MS (ESI⁺) 176.1[MH]⁺.

[0126] 2-Ethyl-3-(4-fluorophenyl)-3H-quinazolin-4-one (IV)

[0127] A solution of 8.50 2-ethyl-benzo[d]1,3]oxazin-4-one (III) (48.5mmol, 1.00 equiv) and 6.27 g 4-fluoroaniline (50.9 mmol, 1.05 equiv)dissolved in 35 mL chloroform was heated to reflux for 12 h, after whichtime TLC indicated no compound III remained (R_(f)=0.51, 20% acetone inhexane). The chloroform was removed in vacuo and the resulting solidsuspended in 18 mL ethylene glycol. A catalytic amount of sodiumhydroxide (86 mg, 2.2 mmol, 0.045 equiv) was added to the mixture, whichwas heated to 140 to 150° C. (external temperature, oil bath). After 10h, the reaction was removed from heat and equilibrated to roomtemperature; upon cooling a precipitate formed. The cooled reactionproduct mixture was acidified with 2 mL aqueous 5% hydrochloric acidsolution and suspended in 20 mL cold water. The solid was collected byvacuum filtration, rinsing with cold water (2×50 mL) and cold isopropylalcohol (2×50 mL). The air-dried solid was recrystallized from isopropylalcohol, affording 10.62 g tan-white needles. m.p. 178.3° C. ¹H NMR(CDCl₃) δ1.25 (t, 3H, J=7.4 Hz), 2.46 (q, 2H, J=7.4 Hz), 7.26 (d, 2H,J=6.4 Hz), 7.27 (d, 2H, J=6.4 Hz), 7.48 (t, 1H, J=6.8 Hz), 7.73-7.81 (m,2H), 8.27 (d, 1H, J=7.96 Hz) ppm. MS (ESI⁺) 269.1 [MH]⁺.

[0128] 2-(1-Bromoethyl)-3-(4-fluorophenyl)-3H-quinazolin-4-one (V).

[0129] To a solution of 7.084 g2-ethyl-3-(4-fluorophenyl)-3H-quinazoline-4-one (IV) (26.40 mmol, 1.000equiv) and 2.60 g sodium acetate (31.7 mmol, 1.20 equiv) dissolved in 30mL glacial acetic acid at 40° C. (external temperature; oil bath) wasadded dropwise by addition funnel a solution of 1.36 mL bromine (26.4mmol, 1.00 equiv) in 5 mL glacial acetic acid over 60 min. Uponcompleted addition of the bromine solution, the reaction was stirred anadditional 60 min, after which time TLC indicated no IV remained(R_(f)=0.44; 40% ethyl acetate in hexane) and the heterogeneous mixturewas poured into 400 mL water. The resulting aqueous, acidic mixture,with precipitate, was stirred vigorously at ambient temperature for twoh. The precipitate was collected by vacuum filtration, rinsing with warm(ca. 40° C.) water (2×50 mL) and cold isopropyl alcohol (50 mL). Thesolid was dried in vacuo over phosphorous pentoxide overnight, affording8.81 g of a white solid.m.p. 179.8° C. ¹H NMR (CDCl₃) δ2.06 (d,J=0.016p, 3H), 4.55 (q, 0.016p, 2H), 7.16 (ddd, 1H, J₁=2.4 Hz, J₂=4.8Hz, J₃=8.4 Hz), 7.24 (dt, 1H, J₁=2.8 Hz, J₂=8.0 Hz), 7.28 (dt, 1H,J₁=2.8 Hz, J₂=8.4 Hz), 7.51-7.58 (m, 2H), 7.80-7.81 (m, 2H), 8.28 (dt,1H, J₁=0.8 Hz, J₂=8.0 Hz) ppm. MS (ESI⁺) 348.0 [MH]⁺.

[0130]3-(4-Fluorophenyl)-2-[1-(2-methoxy-ethylamino)-ethyl]-3H-quinazolin-4-one(VI).

[0131] A solution of 242 mg from2-(1-bromoethyl)-3-(4-fluorophenyl)-3H-quinazolin-4-one (V) (0.697 mmol,1.00 equiv) and 160 μL 1-amino-2-methoxyethane (1.81 mmol, 2.60 equiv)in 5 mL absolute ethanol was heated to reflux for 26 h then concentratedin vacuo to remove the ethanol. The resulting yellow foam waspartitioned between dichloromethane and aqueous saturated sodiumbicarbonate solution (25 mL each). The separated aqueous layer wasextracted again with dichloromethane (20 mL). Combined organic extractswere dried over sodium sulfate, filtered, and concentrated in vacuo toyield a yellow foam. The crude product was purified by chromatography onsilica gel (3.5 cm o.d.×12 cm h) eluting with 5% methanol in chloroform.Fractions containing product at R_(f)=0.31, 5% methanol in chloroform,were combined and concentrated in vacuo to afford 220 mg product as alight yellow foam. ¹H NMR (CDCl₃) δ1.26 (d, 3H, J=6.4 Hz), 2.35 (br s,1H), 2.54 (ddd, 1H, J₁=4.4 Hz, J₂=6.0 Hz, J₃=10.4 Hz), 2.71 (ddd, 1H,J₁=4.0 Hz, J₂=7.2 Hz, J₃=11.2 Hz), 3.27 (s, 3H), 3.36-3.45 (m, 2H), 3.47(q, 1H, J=6.4 Hz), 7.22-7.26 (m, 4H), 7.46 (ddd, 1H, J₁=1.6 Hz, J₂=6.8Hz, J₃=8.0 Hz), 7.71-7.78 (m, 2H), 8.25 (dd, 1H, J₁=1.2 Hz, J₂=8.0 Hz)ppm. MS (ESI⁺) 342.2 [MH]⁺

[0132] Compound 1.01.

[0133] To a solution of 130 mg3-(4-fluorophenyl)-2-[1-(2-methoxy-ethylamino)-ethyl]-3H-quinazolin-4-one(VI) (0.381 mmol, 1.00 equiv), 59 μL triethylamine (0.419 mmol, 1.10equiv), and 2 mg DMAP (16 μmol, 0.04 equiv) dissolved in 3 mL1,4-dioxane at room temperature was added 79 μL neat decanoyl chloride(0.381 mmol, 1.00 equiv); a colorless precipitate developed. Thereaction mixture was stirred overnight at room temperature thenconcentrated in vacuo to remove the dioxane. The resulting concentratewas partitioned between dichloromethane and aqueous saturated sodiumbicarbonate solution (20 mL each). The separated aqueous layer wasextracted again with dichloromethane (15 mL) and the combined organicextracts dried over sodium sulfate, filtered, and concentrated in vacuoto yield a yellow, glassy oil. The crude product was purified bychromatography on silica gel (2.5 cm o.d.×10 cm h) eluting with agradient of 20 to 25% ethyl acetate in hexane. Fractions containingproduct at R_(f)=0.84, 5% methanol in chloroform, were combined andconcentrated in vacuo to afford 120 mg of a colorless solid. m.p. 71.4°C. ¹H NMR (d₆-DMSO; T=140° C.) δ0.90 (t, 3H, J=7.2 Hz), 1.18-1.44 (m,14H), 1.44 (d, 3H, J=7.2 Hz), 1.98-2.08 (m, 2H), 3.11 (s, 3H), 3.33-3.52(m, 4H), 5.11 (br q, 1H, J=6.0 Hz), 7.32 (br m, 3H), 7.49 (br m, 1H),7.55 (ddd, 1H, J₁=1.2 Hz, J₂=7.6 Hz, J₃=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz),7.85 (ddd, 1H, J₁=1.2 Hz, J₂=7.2 Hz, J₃=8.4 Hz), 8.15 (dd, 1H, J₁=1.6Hz, J₂=8.0 Hz) ppm. At room temperature, compound exists as a mixture ofcis/trans amide rotamers, ca. 1:1 determined by integration ofcharacteristic ¹H NMR peaks (CDCl₃, T=25° C.) at δ_(minor) 4.78 (q,1.0H, J=7.2 Hz) and δ_(major) 5.33 (q, 1.2H, J=7.2 Hz) ppm. MS (ESI⁺)496.4 [MH]⁺

Synthesis of Compound 1.02

[0134]

[0135] Compound 1.02 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 1-(2-aminoethyl)pyrrolidine was used in step e instead of2-(dimethylamino)-1-aminoethane. Characterization data for compound 1.02follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound1.01: a mixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.78 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.33 (q, 1.8H, J=7.6 Hz) ppm. MS (ESI⁺) 535.4 [MH]⁺

Synthesis of Compound 1.03

[0136]

[0137] Compound 1.03 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 1-(2-Aminoethyl)morpholine was used in step e instead of2-(dimethylamino)-1-aminoethane. Characterization data for compound 1.03follows: colorless, viscous oil. ¹H NMR (d₆-DMSO; T=140° C.) δ0.89 (t,3H, J=6.8 Hz), 1.18-1.46 (m, 14H), 1.46 (d, 3H, J=6.4 Hz), 1.98-2.08 (m,2H), 2.23-2.34 (m, 5H), 2.47 (ddd, 1H, J₁=6.0 Hz, J₂=8.8 Hz, J₃=14.4Hz), 3.31 (ddd, 1H, J₁=5.6 Hz, J₂=8.4 Hz, J₃=14.4 Hz), 3.39-3.49 (m,5H), 5.10 (br q, 1H), 7.32 (br m, 3H), 7.51 (br m, 1H), 7.56 (ddd, 1H,J₁=0.8 Hz, J₂=J₃=8.0 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.86 (ddd, 1H, J₁=1.6Hz, J₂=7.2 Hz, J₃=8.4 Hz), 8.15 (dd, 1H, J₁=0.8 Hz, J₂=7.2 Hz) ppm. Atroom temperature, compound exists as a mixture of cis/trans amide, ca.4:3 (CDCl₃; T=25° C.) characteristic resonance peaks at δ_(minor) 4.77(q, 1.0H, J=6.4 Hz) and δ_(major) 5.33 (q, 1.3H, J=6.8 Hz) ppm. MS(ESI⁺) 551.5 [MH]⁺

Synthesis of Compound 1.04

[0138]

[0139] Compound 1.04 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 5-(2-Aminoethyl)imidazole was used in step e instead of2-(dimethylamino)-1-aminoethane. Characterization data for compound 1.04follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound1.01: a mixture of cis/trans amide rotamers in ca. 3:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.81 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.05 (q, 2.7H, J=7.2 Hz) ppm. MS (ESI⁺) 532.3 [MH]⁺.

Synthesis of Compound 1.05

[0140]

[0141] Compound 1.05 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein biphenylacetyl chloride was used in step f instead of decanoylchloride. Characterization data for compound 1.05 follows: yellow,viscous oil. ¹H NMR similar to spectrum for compound 1.01: a mixture ofcis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.) characteristicresonance peaks at δ_(minor) 4.89 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.32(q, 1.8H, J=6.8 Hz) ppm. MS (ESI⁺) 549.2 [MH]⁺

Synthesis of Compound 1.06

[0142]

[0143] Compound 1.06 was prepared following the synthesis of 1.01described above. Method 1 was followed for the synthetic sequence,wherein biphenylcarbonyl chloride was used in step f instead of decanoylchloride. Characterization data for compound 1.06 follows: white solid.m.p.=147.3° C. ¹H NMR similar to spectrum for compound 1.01: a mixtureof cis/trans amide rotamers in ca. 3:1 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at δ_(minor) 5.02 (br q,1.0H) and δ_(major) 5.43 (br q, 3.0H) ppm. MS (ESI⁺) 535.2 [MH]⁺

Synthesis of Compound 1.07

[0144]

[0145] Compound 1.07 was prepared following the synthesis of 1.01described above. Method I was followed for the synthetic sequence,wherein 3-(3-Aminopropyl)-(3H)-imidazole was used in step e instead of2-(Dimethylamino)-1-amino ethane. Characterization data for compound1.07 follows; colorless, viscous oil. ¹H NMR similar to spectrum forcompound 1.01: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃;T=25° C.) determined by integration of characteristic resonance peaks atδ_(minor) 4.77 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.28 (q, 1.1H, J=7.6Hz) ppm. MS (ESI⁺) 546.3 [MH]⁺

Synthesis of Compound 1.08

[0146]

[0147] Compound 1.08 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 1-(3-Aminopropyl)morpholine was used in step e instead of2-(Dimethylamino)-1-aminoethane. Characterization data for compound 1.08follows: pale yellow glass. ¹H NMR similar to spectrum for compound1.01: a mixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)determined by integration of characteristic resonance peaks at δ_(minor)4.77 (q, 1.0H, J=6.4 Hz) and δ_(major) 5.38 (q, 1.8H, J=7.2 Hz) ppm. MS(ESI⁺) 565.4 [MH]⁺

Synthesis of Compound 1.09

[0148]

[0149] Compound 1.09 was prepared following the synthesis of 1.01described above. Method 1 was followed for the synthetic sequence,wherein biphenylcarbonyl chloride was used in step f instead of decanoylchloride. Characterization data for compound 1.09 follows: white solid.m.p.=153.0° C. ¹H NMR (d₆-DMSO; T=140° C.) δ1.42 (d, 3H, J=7.2 Hz), 2.07(s, 6H), 2.26 (ddd, 1H, J₁=5.6 Hz, J₂=9.2 Hz, J₃=12.4 Hz), 2.46 (ddd,1H, J₁=5.2 Hz, J₂=9.2 Hz, J₃=14.4 Hz), 3.36 (d, 1H, J=15.2 Hz), 3.38(ddd, 1H, J₁=5.2 Hz, J₂=8.8 Hz, J₃=14.8 Hz), 3.49 (ddd, 1H, J₁=6.0 Hz,J₂=9.2 Hz, J₃=15.2 Hz), 3.50 (d, 1H, J=15.2 Hz), 5.15 (q, 1H, J=6.8 Hz),7.12 (d, 2H, J=7.6 Hz), 7.20 (t, 1H, J=7.2 Hz), 7.26 (dd, 2H, J₁=7.2 Hz,J₂=7.6 Hz), 7.36 (br m, 3H), 7.53 (br m, 1H), 7.56 (ddd, 1H, J₁=1.2 Hz,J₂=7.2 Hz, J₃=8.0 Hz), 7.72 (d, 1H, J=7.2 Hz), 7.87 (ddd, 1H, J₁=1.6 Hz,J₂=7.2 Hz, J₃=8.4 Hz), 8.16 (dd, 1H, J₁=1.6 Hz, J₂=8.0 Hz) ppm. At roomtemperature, compound exists as a mixture of cis/trans amide rotamers,ca. 2:1 (CDCl₃; T=25° C.) determined by integration of characteristicresonance peaks at δ_(minor) 4.84 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.30(q, 2.1H, J=6.8 Hz) ppm. MS (ESI⁺) 473.3 [MH]⁺

Synthesis of Compound 1.10

[0150]

[0151] Compound 1.10 was prepared following the synthesis of 1.01described above. Method 1 was followed for the synthetic sequence,wherein 5-(2-Aminoethyl)imidazole was used in step e instead of2-(Dimethylamino)-1-aminoethane. Characterization data for compound 1.10follows: yellow, viscous oil. ¹H NMR similar to spectrum for compound1.01: a mixture of cis/trans amide rotamers in ca. 3:2 (CDCl₃; T=25° C.)determined by integration of characteristic resonance peaks at δ_(minor)4.77 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.37 (q, 1.6H, J=6.8 Hz) ppm. MS(ESI⁺) 577.4 [MH]⁺

Synthesis of Compound 1.11

[0152]

[0153] Compound 1.11 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein (4-methylphenyl)acetyl chloride was used in step f instead ofdecanoyl chloride. Characterization data for compound 1.11 follows:white solid. m.p. 188.3° C. ¹H NMR similar to spectrum for compound1.09: a mixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)determined by integration of characteristic resonance peaks at δ_(minor)5.02 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.47 (q, 1.9H, J=7.2 Hz) ppm. MS(ESI⁺) 487.3 [MH]⁺

Synthesis of Compound 1.12

[0154]

[0155] Compound 1.12 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein (4-bromophenyl)acetyl chloride was used in step f instead ofdecanoyl chloride. Characterization data for compound 1.12 follows:colorless glass. ¹H NMR similar to spectrum for compound 1.09: a mixtureof cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at 67 _(minor) 4.82 (q,1.0H, J=7.2 Hz) and δ_(major) 5.27 (q, 2.3H, J=6.8 Hz) ppm. MS (ESI⁺)551.2 [MH]⁺

Synthesis of Compound 1.13

[0156]

[0157] To a solution of 112 mg zinc(II) bromide (500 μmol, 10 equiv) at0° C. was added 1.0 mL 1-propenylmagnesium bromide solution in 0.5 mLTHF (0.5 M; 500 μmol, 10 equiv). The resulting white, cloudy mixture wasstirred at 0° C. for 60 min before a solution of 27 mg 1.12 (49 μmol,1.0 equiv) and 4 mg bis-dppf palladium(II) dichloride (5 μmol, 0.1equiv) dissolved in 0.5 mL THF was added all at once by cannulation. Thereaction mixture was stirred at room temperature for 14 h, then heatedto 60° C. (external temperature, oil bath) to drive the reaction towardcompletion. After 2 h at 60° C., 5 mL saturated aqueous ammoniumchloride solution was added to the cooled (0° C.) reaction mixture. Theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic separations dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield a yellow film. The crude product waspurified by flash column chromatography on silica gel (3.5 cm o.d.×10 cmh) eluting with 5% methanol in chloroform to yield 8 mg product olefinas a colorless film. The product was isolated as a mixture of olefinisomers, which were separated by preparative HPLC (reverse phase,CH₃CN:H₂O). Compound 1.13 eluted before the trans olefin isomer 1.14. ¹HNMR similar to spectrum for compound 1.09: a mixture of cis/trans amiderotamers in ca. 2:1 (CDCl₃; T=25° C.) determined by integration ofcharacteristic resonance peaks at δ_(major) 4.85 (q, 1.9H, J=6.8 Hz) andδ_(minor) 5.13 (q, 1.0H, J=7.2 Hz) ppm. MS (ESI⁺) 513.2 [MH]⁺

Synthesis of Compound 1.14

[0158]

[0159] Compound 1.14 was prepared coincidentally with compound 1.12 andisolated by preparative HPLC as the second product to elute. ¹H NMRsimilar to spectrum for compound 1.09: a mixture of cis/trans amiderotamers in ca. 2:1 (CDCl₃; T=25° C.) determined by integration ofcharacteristic resonance peaks at δ_(major) 4.83 (q, 1.8H, J=7.2 Hz) andδ_(minor) 5.12 (q, 1.0H, J=7.6 Hz) ppm. MS (ESI⁺) 513.2 [MH]⁺

Synthesis of Compound 1.15

[0160]

[0161] Hydrogen gas was introduced by balloon to a nitrogen-purged,evacuated flask charged with 4.8 mg 1.13 and 1.14 (9.4 μmol, 1.0 equiv)and 5.0 mg palladium on activated carbon (10% wt Pd; 4.7 μmol, 0.5equiv) suspended in 2.0 mL methanol at room temperature. The reactionwas stirred at room temperature for 18 h then filtered through a pad ofcelite. The filtrate was concentrated in vacuo then purified by columnchromatography on silica gel (2.0 cm o.d.×8 cm h) eluting with 5%methanol in chloroform. Fractions containing product were concentratedin vacuo to afford 4.5 mg of a colorless film. ¹H NMR similar tospectrum for compound 1.09: a mixture of cis/trans amide rotamers in ca.3:2 (CDCl₃; T=25° C.) determined by integration of characteristicresonance peaks at δ_(major) 4.83 (q, 1.4H, J=6.8 Hz) and δ_(minor) 5.20(q, 1.0H, J=7.2 Hz) ppm. MS (ESI⁺) 515.3 [MH]⁺

Synthesis of Compound 1.16

[0162]

[0163] A degassed (3× freeze-evacuate-thaw cycles) biphasic mixture of27.0 mg 1.12 (49.0 μmol, 1.00 equiv), 34.0 mg 4-fluorophenylboronic acid(245 μmol, 5.00 equiv), and 3.0 mg tetrakistriphenylphosphinepalladium(0) (2.5 μmol, 0.05 equiv) in 3.0 mL toluene and 3.0 mL 2Maqueous sodium carbonate was heated to 100° C. (external temperature,oil bath). After 4 h, MS indicated no compound 1.12 remained and theseparated aqueous layer was extracted with 50% ethylacetate in hexane(2×15 mL). Combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo to yield a yellow oil. The crudematerial was purified by chromatography on silica gel (3.5 cm o.d.×12 cmh) eluting with 5% methanol in chloroform. Fractions containing productwere combined and concentrated in vacuo to afford 27.0 mg product as acolorless, viscous oil. ¹H NMR similar to spectrum for compound 1.09: amixture of cis/trans amide rotamers in ca. 3:2 (CDCl₃; T=25° C.)determined by integration of characteristic resonance peaks at δ_(major)4.90 (q, 1.3H, J=7.2 Hz) and δ_(minor) 5.30 (q, 1.0H, J=7.2 Hz) ppm. MS(ESI⁺) 567.2 [MH]⁺.

Synthesis of Compound 1.17

[0164]

[0165] Compound 1.17 was prepared following the synthesis of 1.01described above. Method 1 was followed for the synthetic sequence,wherein 2-methoxy-1-aminoethane was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.17 follows: beige solid. m.p.=153.8° C. ¹H NMR similar tospectrum for compound 1.09: a mixture of cis/trans amide rotamers in ca.2:1 (CDCl₃; T=25° C.) determined by integration of characteristicresonance peaks at δ_(minor) 4.89 (q, 1.0H, J=6.4 Hz) and δ_(major) 5.33(q, 1.8H, J=6.8 Hz) ppm. MS (ESI⁺) 536.2 [MH]⁺

Synthesis of Compound 1.18

[0166]

[0167] Compound 1.18 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 1-(2-aminoethyl)morpholine was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.18 follows: colorless, viscous oil. ¹H NMR similar tospectrum for compound 1.09: a mixture of cis/trans amide rotamers in ca.2:1 (CDCl₃; T=25° C.) determined by integration of characteristicresonance peaks at δ_(minor) 4.88 (q, 1.0H, J=6.8 Hz) and δ_(major) 5.32(q, 1.7H, J=7.2 Hz) ppm. MS (ESI⁺) 591.3 [MH]⁺

Synthesis of Compound 1.19

[0168]

[0169] Compound 1.19 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 2-ethoxy-1-aminoethane was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.19 follows: light yellow, glassy solid. m.p.=150.6° C. ¹H NMR(d₆-DMSO; T=140° C.) δ0.98 (t, 3H, J=6.8 Hz), 1.43 (d, 3H, J=6.8 Hz),3.29-3.63 (m, 8H), 5.18 (q, 1H, J=6.0 Hz), 7.20 (d, 2H, J=7.6 Hz),7.27-7.36 (m, 3H), 7.41-7.47 (m, 3H), 7.49-7.64 (m, 6H), 7.72 (d, 1H,J=8.0 Hz), 7.85 (ddd, 1H, J₁=1.6 Hz, J₂=8.2 Hz, J₃=8.6 Hz), 8.15 (d, 1H,J=8.0 Hz) ppm. At room temperature, compound exists as a mixture ofcis/trans amide rotamers, ca. 2:1 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at δ_(minor) 4.87 (q,1.0H, J=6.8 Hz) and δ_(major) 5.33 (q, 2.1H, J=7.2 Hz) ppm. MS (ESI⁺)550.2 [MH]⁺

Synthesis of Compound 1.20

[0170]

[0171] Compound 1.20 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 3-aminopropionitrile was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.20 follows: colorless glass. ¹H NMR similar to spectrum forcompound 1.19: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃;T=25° C.) determined by integration of characteristic resonance peaks atδ_(A) 4.94 (q, 1.0H, J=6.8 Hz) and δ_(B) 5.14 (q, 1.0H, J=7.6 Hz) ppm.MS (ESI⁺) 530.2 [MH]⁺

Synthesis of Compound 1.21

[0172]

[0173] Compound 1.21 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 2-isopropoxy-1-aminoethane was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.21 follows: faint yellow glass. ¹H NMR similar to spectrumfor compound 1.19: a mixture of cis/trans amide rotamers in ca. 3:1(CDCl₃; T=25° C.) determined by integration of characteristic resonancepeaks at δ_(minor) 4.88 (q, 1.0H, J=6.7 Hz) and δ_(major) 5.30 (q, 2.9H,J=7.0 Hz) ppm. MS (ESI⁺) 564.2 [MH]⁺

Synthesis of Compound 1.22

[0174]

[0175] Compound 1.22 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 2-aminomethylpyridine was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.22 follows: colorless glass. ¹H NMR similar to spectrum forcompound 1.19: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃;T=25° C.) determined by integration of characteristic resonance peaks atδ_(A) 5.13 (q, 1.0H, J=6.4 Hz) and δ_(B) 5.46 (q, 1.0H, J=8.0 Hz) ppm.MS (ESI⁺) 569.3 [MH]⁺

Synthesis of Compound 1.23

[0176]

[0177] Compound 1.23 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 2-aminomethylpyridine was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.23 follows: colorless glass. ¹H NMR similar to spectrum forcompound 1.19: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃;T=25° C.) determined by integration of characteristic resonance peaks atδ_(A) 5.13 (q, 1.0H, J=6.4 Hz) and δ_(B) 5.46 (q, 1.0H, J=8.0 Hz) ppm.MS (ESI⁺) 569.3 [MH]⁺

Synthesis of Compound 1.24

[0178]

[0179] Compound 1.24 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 3-(3-aminopropyl)imidazole was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and biphenylacetyl chloride wasused in step f instead of decanoyl chloride. Characterization data forcompound 1.24 follows: colorless oil. ¹H NMR similar to spectrum forcompound 1.19: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃;T=25° C.) determined by integration of characteristic resonance peaks atδ_(A) 4.89 (q, 1.0H, J=6.6 Hz) and δ_(B) 5.29 (q, 1.1H, J=7.1 Hz) ppm.MS (ESI⁺) 569.3 [MH]⁺.

Synthesis of Compound 1.25

[0180]

[0181] To a mixture of 175 mg 1.19 (318 μmol, 1.00 equiv) and 500 mgzinc powder (7.65 mmol, 24.0 equiv) suspended in 3.0 mL glacial aceticacid at 40° C. (external temperature, oil bath) was added ca. 200 μLconcentrated aqueous hydrochloric acid (5 drops by pipet, 18 M; 3.6mmol). The resulting beige, cloudy reaction mixture evolved gas and wasstirred at 40° C. for 15 min, then decanted from the suspendedsolids/zinc and neutralized with concentrated aqueous sodium hydroxideto pH>12. The aqueous, alkaline solution was extracted withdichloromethane (3×20 mL). Combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo to yield acolorless oil. The crude material was purified by chromatography onsilica gel (3.5 cm o.d.×10 cm h) eluting with 2% methanol in chloroform.Fractions containing product at R_(f)=0.52, 10% methanol in chloroform,were combined and concentrated in vacuo to afford 83 mg of a colorlessoil. ¹H NMR similar to spectrum for compound 1.19: a mixture ofcis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at δ_(minor) 4.62 (q,1.0H, J=7.1 Hz) and δ_(major) 5.31 (q, 2.1H, J=7.0 Hz) ppm. MS (ESI⁺)536.3 [MH]⁺

Synthesis of Compound 1.26

[0182]

[0183] Compound 1.26 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 2-ethoxy-1-aminoethane was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and (4-trifluoromethylphenyl)aceticacid was used, with EDC and catalytic HOBT, in step f instead ofdecanoyl chloride. Characterization data for compound 1.26 follows:colorless oil. ¹H NMR similar to spectrum for compound 1.19: a mixtureof cis/trans amide rotamers in ca. 5:2 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at δ_(minor) 4.85 (q,1.0H, J=6.8 Hz) and δ_(major) 5.33 (q, 2.6H, J=6.8 Hz) ppm. MS (ESI⁺)542.2 [MH]⁺

Synthesis of Compound 1.27

[0184]

[0185] Compound 1.27 was prepared following the synthesis of compound1.01 described above. Method 1 was followed for the synthetic sequence,wherein 3-methylaminopyridine was used in step e instead of2-(N,N-dimethylamino)-1-aminoethane, and (4-trifluoromethylphenyl)aceticacid was used, with EDC and catalytic HOBT, in step f instead ofdecanoyl chloride. Characterization data for compound 1.27 follows:colorless oil. ¹H NMR similar to spectrum for compound 1.19, a mixtureof cis/trans amide rotamers in ca. 6:5 (CDCl₃; T=25° C.) determined byintegration of characteristic resonance peaks at δ_(minor) 4.99 (q,1.0H, J=6.6 Hz) and δ_(major) 5.37 (q, 1.2H, J=7.2 Hz) ppm. MS (ESI⁺)561.2 [MH]⁺

Synthesis of Compound 1.28

[0186]

[0187] Compound 1.28 was prepared following the synthesis of compound1.01. MS(ESI⁺) 533.3, 534.3. ¹H NMR (DMSO, T=140° C.) 0.87 (t, 3H, J=7.0Hz), 1.26 (m, 14H), 1.66 (m, 4H), 2.22 (m, 2H), 2.49-2.76 (m, 6H), 3.51(t, 2H, J=3.3 Hz), 3.87 (s, 3H), 4.24 (s, 2H), 7.11 (m, 2H), 7.31 (m,2H), 7.51 (m, 1H), 7.60 (m, 1H), 7.80 (m, 1H), 8.13 (m, 1H). MS(ESI⁺)533.8 (MH⁺).

Synthesis of Compound 1.29

[0188]

[0189] Compound 1.29 was prepared following the synthesis of compound1.01. Colorless viscous oil; mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.82 (q, 1H, J=7.5 Hz), 5.37 (q, 1H, J=7.5Hz). MS(ESI⁺) 547.2 (MH⁺). Anal. (C₂₃H₂₈N₄O₂) cal. C 72.49H 8.48, N10.25. Found C 72.62, H 8.44, N 10.12.

Synthesis of Compound 1.30

[0190]

[0191] Compound 1.30 was prepared following the synthesis of 1.01.Yellow solid. Mixture of cis/trans amide rotamers(l/1), determined by ¹HNMR (CDCl₃) 1.40 (d, 3H, J=6.8 Hz), 1.46 (d, 3H, J=6.8 Hz). MS(ESI⁺)561.2 (MH⁺).

Synthesis of Compound 1.31

[0192]

[0193] Compound 1.31 was prepared following the synthesis of 1.01.Colorless viscous oil; mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.88 (q, 1H, J=7.2 Hz), 5.38 (q, 1H, J=7.2Hz). MS(ESI⁺) 575.5 (MH⁺). Anal. (C₃₅H₅₀N₄O₃) cal. C 73.14H 8.77, N9.75. Found C 72.45, H 8.75, N 9.08.

Synthesis of Compound 1.32

[0194]

[0195] Compound 1.32 was prepared following the synthesis of 1.01.Colorless viscous oil; mixture of cis/trans amide rotamers (2/3),determined by ¹H NMR (CDCl₃) 4.87 (q, 1H, J=7.2 Hz), 5.38 (q, 1H, J=7.2Hz). MS(ESI⁺) 522.3 (MH⁺). Anal. (C₃₁H₄₃N₃O₄) cal. C 71.37H 8.31, N8.05. Found C 71.13, H 8.42, N 8.02.

Synthesis of Compound 1.33

[0196]

[0197] Compound 1.33 was prepared following the synthesis of 1.01.Yellow solid. m.p. 96.9° C. mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.87 (q, 1H, J=7.2 Hz), 5.38 (q, 1H, J=7.2Hz). MS(ESI⁺) 605.3 (MH⁺). Anal. (C₃₇H₃₇FN₄O₃.C₄H₈O₂) cal. C 71.08H6.55, N 8.09. Found C 71.96, H 6.19, N 8.47.

Synthesis of Compound 1.34

[0198]

[0199] Compound 1.34 was prepared following the synthesis of 1.01. whitesolid. m.p. 116.3° C. mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.96 (q, 1H, J=7.2 Hz), 5.38 (q, 1H, J=7.2Hz). MS(ESI⁺) 587.3 (MH⁺). Anal. (C₃₇H₃₈N₄O₃) cal. C 75.74H 6.53, N9.55. Found C 75.05, H 6.56, N 9.35.

Synthesis of Compound 1.35

[0200]

[0201] Compound 1.35 was prepared following the synthesis of 1.01.yellow solid. Mixture of cis/trans amide rotamers (3/8), determined by¹H NMR (CDCl₃) 4.89 (m, 1H), 5.38 (m, 1H). MS(ESI⁺) 575.3 (MH⁺). Anal.(C₃₆H₃₅FN₄O₂.C₄H₈O₂) cal. C 72.49H 6.54, N 8.45. Found C 72.77, H 6.10,N 8.89.

Synthesis of Compound 1.36

[0202]

[0203] Compound 1.36 was prepared following the synthesis of 1.01. whitesolid; m.p. 61.3° C. mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.92 (q, 1H, J=7.2 Hz), 5.32 (q, 1H, J=7.2Hz).MS(ESI⁺) 591.3 (MH⁺). Anal. (C₃₆H₃₈N₄O₄) cal. C 73.20H 6.48, N 9.48.Found C 72.92, H 6.46, N 9.29.

Synthesis of Compound 1.37

[0204]

[0205] Compound 1.37 was prepared following the synthesis of 1.01. whitesolid; mixture of cis/trans amide rotamers (1/2), determined by ¹H NMR(CDCl₃) 4.86 (q, 1H, J=7.2 Hz), 5.32 (q, 1H, J=7.2 Hz).MS(ESI⁺) 515.3(MH⁺). Anal. (C₃₁H₃₅FN₄O₂) cal. C 72.35H 6.85, N 10.89. Found C 72.11, H6.92, N 10.71.

Synthesis of Compound 1.38

[0206]

[0207] Compound 1.38 was prepared following the synthesis of 1.01. whitesolid; mixture of cis/trans amide rotamers (1/1.7), determined by ¹H NMR(CDCl₃) 4.85 (q, 1H, J=7.2 Hz), 5.30 (q, 1H, J=7.2 Hz).MS(ESI⁺) 545.3(MH⁺). Anal. (C₃₂H₃₇FN₄O₃) cal. C 70.57H 6.85, N 10.29. Found C 70.33, H6.90, N 10.13.

Synthesis of Compound 1.39

[0208]

[0209] Compound 1.39 was prepared following the synthesis of 1.01. whitesolid; mixture of cis/trans amide rotamers (1/1), determined by ¹H NMR(CDCl₃) 4.95 (q, 1H, J=7.2 Hz), 5.32 (q, 1H, J=7.2 Hz).MS(ESI⁺) 562.3(MH⁺). Anal. (C₃₅H₃₅N₃O₄) cal. C 74.84H 6.28, N 7.48. Found C 74.56, H6.26, N 7.30.

Synthesis of Compound 1.40

[0210]

[0211] Compound 1.40 was prepared following the synthesis of 1.01. Whitesolid; mixture of cis/trans amide rotamers (2/1), determined by ¹H NMR(CDCl₃) 4.70 (m, 1H), 5.38 (t, 1H, J=7.0 Hz).MS(ESI⁺) 604.3 (MH⁺). Anal.(C₃₈H₄₁N₃O₄) cal. C 75.60H 6.84, N 6.96. Found C 74.98, H 6.82, N 6.72.

Synthesis of Compound 1.42

[0212]

[0213] Compound 1.42 was prepared following the synthesis of 1.01. whitesolid; mixture of cis/trans amide rotamers (1/2), determined by ¹H NMR(CDCl₃) 4.86 (q, 1H, J=7.3 Hz), 5.30 (q, 1H, J=7.3 Hz).MS(ESI⁺) 644.2(MH⁺). Anal. (C₃₃H₃₀₁N₃O₃) cal. C 61.59H 4.70, N 6.53. Found C 61.63, H4.73, N 6.36.

Synthesis of Compound 1.43

[0214]

[0215] The mixture of 1.42 (1 mmol, 0.643 g) and CuCN (3 mmol, 0.27 g)in 10 0.ml of DMF was heated to 130° C. for 10 h. After evaporating thesolvent, the residue was dissolved in CH₂Cl₂, the organic layer waswashed by water, brine, dried over NaSO₄ and removed in vacuo to give asticky oil which was purified by chromatography to afford a white solid;mixture of cis/trans amide rotamers (1/2), determined by ¹H NMR (CDCl₃)4.75 (q, 1H, J=7.3 Hz), 5.28 (q, 1H, J=7.3 Hz).MS(ESI⁺) 543.2 (MH⁺).Anal. (C₃₄H₃₀N₄O₃) cal. C 75.26H 5.57, N 10.32. Found C 75.00, H 5.59, N10.19.

Synthesis of Compound 1.44

[0216]

[0217] Compound 1.44 was prepared following the synthesis of 1.01. Whitesolid. ¹H NMR (CDCl₃) 1.40 (d, 3H, J=7.3 Hz), 3.05 (m, 1H), 3.12 (s,3H), 3.25 (m, 1H), 3.55-3.70 (m, 2H), 3.77 (d, 1H, J=15 Hz), 3.9 (d, 1H,J=15 Hz), 5.08 (d, 1H, 12 Hz), 5.88 (m, 2H), 7.28-7.35 (m, 5H), 7.42 (m,2H), 7.57 (m, 5H), 7.72 (m, 1H), 7.80 (m, 1H), 8.32 (m, 1H), 8.55 (m,2H). MS(ESI⁺) 533.3 (MH⁺).

Synthesis of Compound 1.45

[0218]

[0219] The mixture of 1.43 (0.1 mmol, 0.054 g) and 30% H₂O₂ (0.6 mmol)in 1 mL of DMF and 1 ml of dioxane was stirred at room temperature for 1h. Usual work up gave the give a white solid; mixture of cis/trans amiderotamers (1/2), determined by ¹H NMR (CDCl₃) 4.95 (q, 1H, J=7.3 Hz),5.15 (q, 1H, J=7.3 Hz).MS(ESI⁺) 561.3(MH⁺). Anal. (C₃₄H₃₂N₄O₄.C₄H₈O)cal. C 70.35H 6.21 N 8.64. Found C 70.98, H 5.99, N 9.14.

Synthesis of Compound 1.47

[0220]

[0221] Compound 1.47 was prepared following the synthesis of 1.01,mixture of cis/trans amide rotamers (1/17), determined by ¹H NMR (CDCl₃)1.35 (d, 3H, J=7.3 Hz), 1.42 (d, 3H, J=7.3 Hz).MS(ESI⁺) 534.2 (MH⁺).Anal. (C₃₃H₃₁N₃O₄) cal. C 74.28H 5.86, N 7.87. Found C 73.83, H 5.93, N7.73.

Synthesis of Compound 1.48

[0222]

[0223] Compound 1.48 was prepared following the synthesis of 21. whitesolid, mixture of cis/trans amide rotamers (1/5), determined by ¹H NMR(CDCl₃) 4.72 (q, 1H, J=7.0 Hz), 5.25 (q, 1H, J=7.0 Hz).MS(ESI⁺) 557.3(MH⁺). Anal. (C₃₅H₃₂N₄O₃) cal. C 75.52H 5.79, N 10.06. Found C 75.03, H5.92, N 9.96

Synthesis of Compound 1.49

[0224]

[0225] Compound 1.49 was prepared following the synthesis of 1.01, whitesolid, m.p. 98.1° C., mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.72 (q, 1H, J=7.0 Hz), 5.25 (q, 1H, J=7.0Hz).MS(ESI⁺) 576.3 (MH⁺). Anal. (C₃₆H₃₇N₃O₄) cal. C 75.11H 6.48, N 7.30.Found C 75.08, H 6.59, N 7.27.

Synthesis of Compound 1.50

[0226]

[0227] Compound 1.50 was prepared following the synthesis of 1.01, whitesolid, ¹H NMR (CDCl₃) 1.24 (d, 3H, J=6.8 Hz), 1.46 (t, 3H, J=6.9 Hz),3.64 (s, 2H), 4.09 (q, 2H, J=6.9 Hz), 4.83 (m, 1H), 6.90 (m, 1H), 7.05(m, 2H), 7.17 (m, 1H), 7.35-7.61 (m, 7H), 7.63 (m, 5H), 8.25 (m,1H).MS(ESI⁺) 504.2 (MH⁺). Anal. (C₃₂H₂₉N₃O₃) cal. C 76.32H 5.80, N 8.34.Found C 75.85, H 5.88, N 8.14

Synthesis of Compound 1.51

[0228]

[0229] Compound 1.51 was prepared following the synthesis of 1.01, whitesolid, ¹H NMR (CDCl₃) 1.05 (t, 3H, J=7.0 Hz), 1.40 (t, 3H, J=6.92 Hz),2.81 (m, 2H), 3.18 (m, 2H), 3.80 (m, 2H), 3.91 (d, 1H, J=15 Hz), 4.0 (m,2H), 4.03 (d, 1H, J=15 Hz), 6.11 (m, 1H), 6.42 (m, 1H), 6.47 (m, 1H),7.01 (m, 3H), 7.22-7.58 (m, 14H), 7.64 (m, 1H), 7.75 (m, 1H), 8.27 (d,1H, J=8 Hz). MS(ESI⁺) 638.3 (MH⁺). Anal. (C₄₁H₃₉N₃O₄) cal. C 77.21H6.16, N 6.59. Found C 77.28, H 6.15, N 6.58.

Synthesis of Compound 1.52

[0230]

[0231] Compound 1.53 was synthesized in a manner similar to that usedfor the synthesis of 1.01. Under N₂, the mixture of pyridine-4-boronicacid (0.053 g, 0.43 mmol), 1.52 (0.050 g, 0.087 mmol) and Pd(PPh₃)₄(0.010 g, 0.009 mmol) in toluene (4 mL) and 3M Na₂CO₃ (4 mL) was heatedto 110° C. for 3 h. The organic layer was washed with water, dried overNaSO₄ and evaporated to give a oil which was purified by chromatographyto afford compound 1.53 as a white solid (15 mg). MS(ESI⁺) 577.3 (MH⁺).

Synthesis of Compound 1.54

[0232]

[0233] Under N₂, the mixture of 3,4-difluorophenylboronic acid (0.131 g,0.83 mmol), compound 1.52 (0.050 g, 0.087 mmol) and Pd(OAc)₂(0.016 g,0.071 mmol) in DME (3 mL) and 3M Na₂CO₃ (2 mL) was heated to 90° C. for3 h. The aqueous layer was extracted with CH₂Cl₂, the combined organicextracts was dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to give a white solid (71 mg,). ¹H NMR(DMSO, T=140° C.) 0.96 (d, 3H, J=6.8 Hz), 1.36 (t, 3H, J=7.2 Hz), 1.42(d, 3H, J=6.4 Hz), 3.31-3.56 (m, 8H), 4.13 (q, 2H, J=6.8 Hz), 5.16 (q,1H, J=6.4 Hz), 7.05 (br, 2H), 7.18-7.61 (m 10H), 7.70 (d, 1H, J=8 Hz),7.84 (t, 1H, J=6.8 Hz), 8.13 (d, 1H, J=8.4 Hz). At room temperature,mixture of cis/trans amide rotamers (1/1), determined by ¹H NMR (CDCl₃)4.95 (q, 1H, J=6.8 Hz), 5.35 (q, 1H, J=6.8 Hz ). MS(ESI⁺) 612.2(MH⁺).Anal. (C₃₆H₃₅F₂N₃O₄) cal. C 70.69H 5.77 N 6.87. Found C 70.22, H 5.71, N6.81.

Synthesis of Compound 1.55

[0234]

[0235] Trifluoroacetic anhydride (0.024 g, 0.113 mmol) was addeddropwise to a mixture of the amine (0.036 g, 0.094 mmol) and Et₃N (0.014g, 0.142 mmol) in CH₂Cl₂ at room temperature. After stirring for 1 h,the organic layer was washed by water, brine, dried over NaSO₄ andremoved in vacuo to give a oil which was purified by chromatography toafford a colorless oil, compound 1.55. ¹H NMR (CDCl₃) 1.06 (t, 3H,J=7.04 Hz), 1.45 (t, 3H, J=7.0 Hz), 1.54 (d, 3H, J=7 Hz), 3.38 (m, 2H),3.58 (t, 2H, J=6.2 Hz), 3.70 (t, 2H, J=6.2 Hz), 4.08 (m, 2H), 5.19 (q,1H, J=7 Hz), 7.01 (m, 2H), 7.14 (m, 1H), 7.32 (m, 1H), 7.51 (m, 1H),7,77 (m, 2H), 8.27 (d, 1H, J=7.3 Hz) MS(ESI⁺) 478.3 (MH⁺).

EXAMPLE 2 Synthesis of Compound 2.01

[0236] The synthesis of 2.01 in five steps from commercially available2-amino-6-methyl-benzoic acid is an example of 3H-quinazolin-4-onesynthesis by Method 2 (see Scheme 2, below).

[0237] 2-Methyl-6-propionylamino-benzoic acid (VIII).

[0238] To a room temperature solution of 4.35 g 2-amino-6-methyl-benzoicacid (VII) (28.8 mmol, 1.00 equiv) dissolved in 25 mL dry DMF was added2.75 mL propionyl chloride (31.7 mmol, 1.10 equiv) dropwise by additionfunnel over 30 min. Upon completed addition of the acid chloride, theheterogeneous reaction mixture was stirred for 3 h at room temperatureand then poured into 200 mL water. The resulting water/DMF mixture, withwhite precipitate, was stirred vigorously at ambient temperature for oneh, after which time the solid was collected by vacuum filtration,rinsing the solid with cold water (2×50 mL). The white solid was driedin vacuo over phosphorous pentoxide overnight to afford 4.65 g of awhite solid. m.p. 152.5° C. ¹H NMR (d₆-DMSO) δ1.06 (t, 3H, J=7.6 Hz),2.29 (q, 2H, J=7.6 Hz), 2.35 (s, 3H), 7.04 (d, 1H, J=7.6 Hz), 7.30 (dd,1H, J₁=7.6 Hz, J₂=8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 9.57 (s, 1H), 13.18(br s, 1H) ppm. MS (ESI⁻) 206.1 [M−H]⁻.

[0239] 2-Ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX)).

[0240] To a mixture of 4.266 g 2-methyl-6-propionylamino-benzoic acid(VIII) (20.58 mmol, 1.00 equiv) and 2.14 mL 4-fluoroaniline (22.6 mmol,1.10 equiv) suspended in 35 mL toluene was added a solution of 1.08 mLphosphorous trichloride (12.3 mmol, 0.598 equiv) dissolved in 10 mLtoluene dropwise by addition funnel over 30 min. The resultingheterogeneous mixture was heated to reflux for 20 h and then cooled toroom temperature and diluted with 100 mL toluene. To the roomtemperature reaction mixture was added 100 mL aqueous 10% sodiumcarbonate solution and the resulting biphase was stirred vigorouslyuntil all solids dissolved. The toluene was removed in vacuo and aprecipitate developed. The solid was collected by filtration, rinsingwith water (2×75 mL). The air-dried solid was purified byrecrystallization from isopropyl alcohol to afford 3.31 g colorlessflakes, dried in vacuo over phosphorous pentoxide. m.p. 170.0° C. ¹H NMR(CDCl₃) δ1.24 (t, 3H, J=7.6 Hz), 2.44 (q, 2H, J=7.6 Hz), 2.84 (s, 3H),7.25 (dd, 1H, J₁=1.6 Hz, J₂=6.4 Hz), 7.27 (2×d, 2×2H, J=6.4 Hz), 7.58(dd, 1H, J₁=1.2 Hz, J₂=8.0 Hz), 7.63 (dd, 1H, J₁=J₂=8.0 Hz) ppm. MS(ESI⁺) 283.2 [MH]⁺.

[0241]2-(1-Bromo-ethyl)-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (X).

[0242] To a mixture of 1.969 g2-ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX) (6.974mmol, 1.000 equiv) and 0.687 g sodium acetate (8.37 mmol, 1.20 equiv) in28 mL glacial acetic acid at 40° C. (external temperature, oil bath) wasadded a solution of 0.372 mL bromine (7.32 mmol, 1.05 equiv) dissolvedin 5 mL glacial acetic acid dropwise by addition funnel over 30 min.After 2 h the reaction solution was poured into 250 mL water. Theresulting mixture was stirred vigorously at room temperature for 1 h,after which time the precipitate was collected by vacuum filtration,rinsing with warm (ca. 40° C.) water (3×50 mL). The solid was dried invacuo over phosphorous pentoxide overnight, affording 2.19 g of a whitesolid. m.p. decomposes upon heating. ¹H NMR (CDCl₃) δ2.04 (d, 3H, J=6.8Hz), 2.82 (s, 3H), 4.51 (q, 1H, J=6.8 Hz), 7.15 (ddd, 1H, J₁=2.4 Hz,J₂=4.4 Hz, J₃=8.4 Hz), 7.23 (dd, 1H, J₁=2.8 Hz, J₂=10.8 Hz), 7.25-7.31(m, 2H), 7.56 (ddd, J₁=2.8 Hz, J₂=4.8 Hz, J₃=8.8 Hz), 7.64 (2×d, 2×1H,J=5.2 Hz) ppm. MS (ESI⁺) 361.1 [MH]⁺.

[0243]3-(4-Fluoro-phenyl)-5-methyl-2-[1-(2-morpholin-4-yl-ethylamino)-ethyl]-3H-quinazolin-4-one(XI).

[0244] A mixture of 0.283 g2-(1-bromo-ethyl)-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (X)(0.784 mmol, 1.00 equiv) and 0.165 mL 1-(2-aminoethyl)morpholine (1.25mmol, 1.60 equiv) in 5 mL ethanol was heated to reflux. After 20 h, theethanol was removed in vacuo and the concentrate partitioned betweendichloromethane and saturated aqueous sodium bicarbonate solution (20 mLea.). The separated aqueous layer was extracted again withdichloromethane (15 mL) and the combined organic extracts dried overmagnesium sulfate, filtered, and concentrated in vacuo to yield a yellowfoam. The crude material was purified by chromatography on silica gel(3.5 cm o.d.×12 cm h) eluting with 5% methanol in chloroform. Fractionscontaining product were combined and concentrated in vacuo to afford 257mg of a pale yellow solid. m.p. 192.9° C. ¹H NMR (CDCl₃) δ1.27 (d, 3H,J=6.4 Hz), 2.26-2.34 (m, 3H), 2.38-2.44 (m, 1H), 2.46-2.52 (m, 2H),2.56-2.70 (m, 2H), 2.82 (s, 3H), 3.39 (q, 1H, J=6.4 Hz), 3.70-3.80 (m,4H), 7.18-7.29 (m, 5H), 7.46 (dd, 1H, J₁=0.8 Hz, J₂=8.0 Hz), 7.61 (dd,1H, J₁=7.6 Hz, J₂=7.8 Hz), ppm. MS (ESI⁺) 411.2 [MH]⁺

[0245] Compound 2.01.

[0246] To a room temperature solution of 127 mg3-(4-fluoro-phenyl)-5-methyl-2-[1-(2-morpholin-4-yl-ethylamino)-ethyl]-3H-quinazolin-4-one(XI) (0.309 mmol, 1.00 equiv), 0.084 mL triethylamine (0.618 mmol, 2.00equiv), and 2.0 mg DMAP (0.016 mmol, 0.052 equiv) dissolved in 3 mLdichloromethane was added 107 mg biphenylacetyl chloride (0.463 mmol,1.50 equiv). The clear, faint yellow-colored reaction mixture wasstirred for 12 h at room temperature then poured into 10 mL saturatedaqueous sodium bicarbonate solution. The separated aqueous layer wasextracted with a second volume of dichloromethane (20 mL). The combinedorganic extracts dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield an orange oil. The crude product waspurified by chromatography on silica gel (3.5 cm o.d.×10 cm h) elutingwith 2% methanol in chloroform. Fractions containing product atR_(f)=0.48, 5% methanol in chloroform, were combined and concentrated invacuo to afford 115 mg product as a faint yellow, viscous oil. ¹H NMR(d₆-DMSO; T=140° C.) δ1.44 (d, 3H, J=6.4 Hz), 2.28-2.42 (m, 5H),2.50-2.60 (m, 1H), 2.77 (s, 3H), 3.38-3.64 (m, 8H), 5.12 (q, 1H, J=6.8Hz), 7.20 (m, 2H), 7.27-7.38 (m, 5H), 7.40-7.47 (m, 3H), 7.51-7.56 (m,3H), 7.58-7.64 (m, 2H), 7.68 (dd, 1H, J₁=J₂=7.6 Hz) ppm. At roomtemperature, compound exists as a mixture of cis/trans amide rotamers,ca. 3:2 by ¹H NMR (CDCl₃; T=25° C.) δ4.84 (q, 1.0H, J=6.8 Hz) & 5.28 (q,1.4H, J=6.8 Hz) ppm. MS (ESI⁺) 605.3 [MH]⁺

Synthesis of Compound 2.02

[0247]

[0248] Compound 2.02 was prepared following the synthesis of 2.01described above. Method 2 was followed for the synthetic sequence,wherein 2-amino-3-methoxy-benzoic acid was used in step a instead of2-amino-6-methylbenzoic acid. Characterization data for compound 2.02follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 3:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.89 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.28 (q, 2.8H, J=7.6 Hz) ppm. MS (ESI⁺) 579.3 [MH]⁺

Synthesis of Compound 2.03

[0249]

[0250] Compound 2.03 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-amino-3-chloro-benzoic acid was used in step a instead of2-amino-6-methylbenzoic acid. Characterization data for compound 2.03follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 3:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.89 (q, 1.0H, J=6.4 Hz) andδ_(major) 5.23 (q, 2.7H, J=6.8 Hz) ppm. MS (ESI⁺) 625.3 [MH]⁺

Synthesis of Compound 2.04

[0251]

[0252] Compound 2.04 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-amino-3-methyl-benzoic acid was used in step a instead of2-amino-6-methyl-benzoic acid. Characterization data for compound 2.04follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 3:2 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.92 (q, 1.0H, J=6.7 Hz) andδ_(major) 5.35 (q, 1.7H, J=7.3 Hz) ppm. MS (ESI⁺) 605.3 [MH]⁺

Synthesis of Compound 2.05

[0253]

[0254] Compound 2.05 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-amino-6-chloro-benzoic acid was used in step a instead of2-amino-6-methyl-benzoic acid. Characterization data for compound 2.05follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.84 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.21 (q, 2.0H, J=6.8 Hz) ppm. MS (ESI⁺) 625.3 [MH]⁺

Synthesis of Compound 2.06

[0255]

[0256] Compound 2.06 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-amino-6-fluoro-benzoic acid was used in step a instead of2-amino-6-methyl-benzoic acid and 2-ethoxy-1-aminoethane was used instep d instead of 1-(2-aminoethyl)morpholine. Characterization data forcompound 2.06 follows: colorless, viscous oil. ¹H NMR similar tospectrum for compound 2.01: a mixture of cis/trans amide rotamers in ca.5:2 (CDCl₃; T=25° C.) characteristic resonance peaks at δ_(minor) 4.87(q, 1.0H, J=6.7 Hz) and δ_(major) 5.27 (q, 2.5H, J=7.0 Hz) ppm. MS(ESI⁺) 568.2 [MH]⁺

Synthesis of Compound 2.07

[0257]

[0258] Compound 2.07 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-ethoxy-1-aminoethane was used in step d instead of1-(2-aminoethyl)morpholine. Characterization data for compound 2.07follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.85 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.29 (q, 1.8H, J=6.6 Hz) ppm. MS (ESI⁺) 564.3 [MH]⁺

Synthesis of Compound 2.08

[0259]

[0260] Compound 2.08 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 4-ethoxyaniline was used in step b instead of 4-fluoroanilineand 2-ethoxy-1-aminoethane was used in step d instead of1-(2-aminoethyl)morpholine. Characterization data for compound 2.08follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 1:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(A) 4.95 (q, 1.1H, J=6.8 Hz) andδ_(B) 5.35 (q, 1.0H, J=6.8 Hz) ppm. MS (ESI⁺) 590.3 [MH]⁺

Synthesis of Compound 2.09

[0261]

[0262] Compound 2.09 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequencewherein butyryl chloride was used in step a instead of propionylchloride, 4-cyanoaniline was used in step b instead of 4-fluoroaniline,and 2-ethoxy-1-aminoethane was used in step d instead of1-(2-aminoethyl)morpholine. Characterization data for compound 2.09follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound2.01: a mixture of cis/trans amide rotamers in ca. 4:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 4.39 (dd, 1.0H, J₁=4.4 Hz,J₂=10.0 Hz) and δ_(major) 5.31 (dd, 3.9H, J₁=J₂=7.2 Hz) ppm. MS (ESI⁺)585.3 [MH]⁺.

Synthesis of Compound 2.10

[0263]

[0264] Compound 2.10 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-aminonicotinic acid was used in step a instead of2-amino-6-methylbenzoic acid, 4-ethoxyaniline was used in step b insteadof 4-fluoroaniline, and 2-ethoxy-1-aminoethane was used in step dinstead of 1-(2-aminoethyl)morpholine. Characterization data forcompound 2.10 follows: light yellow, viscous oil. ¹H NMR similar tospectrum for compound 2.01: a mixture of cis/trans amide rotamers in ca.1:1 (CDCl₃; T=25° C.) characteristic resonance peaks at δ_(minor) 5.04(q, 1.0H, J=6.4 Hz) and δ_(major) 5.41 (q, 1.0H, J=7.2 Hz) ppm. MS(ESI⁺) 577.3 [MH]⁺

Synthesis of Compound 2.11

[0265]

[0266] Compound 2.11 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein butyryl chloride was used in step a instead of propionylchloride, 4-ethoxyaniline was used in step b instead of 4-fluoroaniline,and 2-ethoxy-1-aminoethane was used in step d instead of1-(2-aminoethyl)morpholine. Characterization data for compound 2.11follows: colorless, viscous oil. ¹H NMR (d₆-DMSO; T=140° C.) δ0.80 (t,3H, J=7.6 Hz), 0.94 (t, 3H, J=6.8 Hz), 1.35 (t, 3H, J=6.8 Hz), 1.59-1.70(m, 1H), 2.20-2.30 (m, 1H), 2.77 (s, 3H), 3.22-3.42 (m, 4H), 3.47-3.65(m, 2H), 4.10 (q, 2H, J=6.8 Hz), 5.01 (br q, 1H), 6.98-7.12 (m, 2H),7.15-7.27 (m, 4H), 7.29-7.36 (m, 2H), 7.41-7.47 (m, 2H), 7.51-7.56 (m,3H), 7.59-7.63 (m, 2H), 7.67 (dd, 1H, J₁=7.6 Hz, J₂=7.8 Hz) ppm. At roomtemperature, compound exists as a mixture of cis/trans amide rotamers,ca. 5:3 by ¹H NMR (CDCl₃; T=25° C.) δ_(major) 4.65 (dd, 1.7H, J₁=4.8 Hz,J₂=10.0 Hz) and δ_(minor) 5.39 (dd, 1.0H, J₁=J₂=7.2 Hz) ppm. MS (ESI⁺)604.2 [MH]⁺

Synthesis of Compound 2.12

[0267]

[0268] Compound 2.12 was prepared following the synthesis of compound2.01 described above. Method 2 was followed for the synthetic sequence,wherein 2-aminonicotinic acid was used in step a instead of2-amino-6-methylbenzoic acid, 4-ethoxyaniline was used in step b insteadof 4-fluoroaniline, 2-ethoxy-1-aminoethane was used in step d instead of1-(2-aminoethyl)morpholine, and 4-trifluoromethylphenylacetic acid wasused in step e instead of biphenylacetyl chloride. Characterization datafor compound 2.12 follows: colorless, viscous oil. ¹H NMR (d₆-DMSO;T=140° C.) δ0.96 (t, 3H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz), 1.47 (d, 3H,J=6.4 Hz), 3.29-3.40 (m, 2H), 3.42-3.51 (m, 2H), 3.54-3.64 (m, 2H), 4.11(q, 2H, J=6.8 Hz), 5.20 (q, 1H, J=7.2 Hz), 7.00-7.10 (m, 2H), 7.23-7.41(m, 4H), 7.53-7.60 (m, 3H), 8.50 (dd, 1H, J₁=2.4 Hz, J₂=8.4 Hz), 9.00(dd, 1H, J₁=2.0 Hz, J₂=4.4 Hz) ppm. At room temperature, compound existsas a mixture of cis/trans amide rotamers, ca. 3:2 by ¹H NMR (CDCl₃;T=25° C.) δ_(minor) 5.00 (q, 1.0H, J=6.0 Hz) and δ_(major) 5.38 (q,1.4H, J=7.2 Hz) ppm. MS (ESI⁺) 569.3 [MH]⁺.

Example 3 Synthesis of 3.01

[0269] The synthesis of compound 3.01 in five steps from commerciallyavailable starting materials provides an example of a3H-quinazolin-4-one synthesis in enantiomerically enriched form. Scheme3 provides an overview of the synthetic route, for which theexperimental details follow.

[0270](R)-2-(1-N-BOC-aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-one(XII).

[0271] To a solution of anthranilic acid (411 mg, 3.0 mmol, 1.0 equiv)and N-BOC-D-alanine (568 mg, 3.0 mmol, 1.0 equiv) in 3.0 mL of anhydrouspyridine was added 0.96 mL of triphenylphosphite (1.14 g, 3.6 mmol, 1.2equiv) at room temperature. The resulting yellow solution was stirred at50° C. for 20 h. p-Phenetidine (453 mg, 3.3 mmol, 1.1 equiv) was addedvia syringe. The reaction mixture was stirred for another 2 h at 50° C.,cooled to room temperature, and evaporated in vacuo to remove most ofpyridine. The residue in 15 mL of diethyl ether was washed successivelytwice with 9 mL of 5% aqueous phosphoric acid, twice with 9 mL of 1 MNaOH, once with 5 mL of pH 7 phosphate buffer (0.5 M KH₂PO₄ and 0.5 MK₂HPO₄), and once with 9 mL of brine. The organic layer was dried overNa₂SO₄ and evaporated in vacuo to give a brown residue, which wasrecrystallized from a mixture of 3 mL of EtOAc and 12 mL of heptane togive 0.51 g of compound XII as a white solid. The mother liquor wasconcentrated in vacuo to give a brown residue, which was recrystallizedfrom a mixture of 1 mL of EtOAc and 4 mL of heptane to give a secondcrop of 0.13 g of XII as a light yellow solid. m.p. 143.7° C. ¹H NMR(DMSO-d₆) δ1.19 (d, J=6.4 Hz, 3H), 1.32 (s, 9H), 1.37 (t, J=6.8 Hz, 3H),4.10 (q, J=6.9 Hz, 2H), 4.24 (m, 1H), 7.09 (m, 2H), 7.28 (d, J=8.0 Hz,2H), 7.39 (dd, J=8.4, 2.0 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.69 (d,J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H) ppm. MS(ESI⁺) m/z 410.2 [M+H]⁺.

[0272] (R)-2-(1-Aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-one(XIII).

[0273] To a suspension of XII (9.39 g, 22.9 mmol, 1.0 equiv) in 45 mL ofanhydrous acetonitrile was added 3.43 mL of iodotrimethylsilane (4.82 g,24.1 mmol, 1.05 equiv) dropwise via syringe over 15 min. After stirringfor another 45 min at room temperature, all starting material XII hadbeen consumed. The resulting mixture was partitioned between 50 mL of 1M NH₄OH and 90 mL of ether. The aqueous layer was extracted two moretimes with 30 mL of ether. The combined ether extract was washed oncewith 40 mL of brine. The organic layer was dried over Na₂SO₄ andevaporated in vacuo to give a light gray solid. Recrystallization ofthis crude product from 25 mL of dioxane gave 4.2 g of XIII as a whitesolid. The mother liquor was concentrated in vacuo to give a light graysolid which was triturated with 15 mL of ether to give 1.8 g ofadditional product as a off-white solid. Total yield was 6.0 g. m.p.179.9° C. ¹H NMR (DMSO-d₆) δ1.16 (d, J=6.4 Hz, 3H), 1.38 (t, J=7.0 Hz,3H), 2.25 (br s, 2H), 3.51 (q, J=6.4 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H),7.08 (m, 2H), 7.36 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.70 (d, J=8.0 Hz,1H), 7.85 (t, J=7.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H) ppm. MS (ESI⁺) m/z310.1 [M+H]⁺.

[0274](R)-2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-one (3.01).

[0275] 3-Picolylchloride hydrochloride (4.²7 g, 26 mmol, 1.15 equiv), KI(4.32 g, 26.0 mmol, 1.15 equiv), and 60 mL of DMPU were mixed in a 200mL flask. The mixture was vigorously stirred for 1 h at roomtemperature. To the resulting yellow mixture was added compound XIII(7.0 g, 22.6 mmol, 1.0 equiv) and K₂CO₃ (9.38 g, 67.9 mmol, 3.0 equiv).The mixture was stirred at room temperature for 14 h. Additional3-picolylchloride hydrochloride (740 mg, 4.51 mmol, 0.2 equiv) was addedand the mixture was stirred for another 8 h at room temperature.

[0276] To the above reaction mixture was added4-trifluoromethylphenylacetic acid (5.08 g, 24.9 mmol, 1.1 equiv), HOBT(4.58 g, 33.9 mmol, 1.5 equiv), and 20 mL of dichloromethane at roomtemperature. EDC (13.0 g, 67.8 mmol, 3.0 equiv) was then addedportionwise over 15 min. After the initial gas evolution had subsided,the mixture was stirred vigorously at room temperature for another 14 h.The reaction mixture was poured into a mixture of 180 mL of 10% citricacid and 150 mL of ether. The aqueous layer was extracted twice with 100mL of ether. The combined ether extract was washed twice with 60 mL of2% citric acid, twice with 50 mL of saturated NaHCO₃, and once with 100mL of brine. The organic layer was dried over Na₂SO₄ and evaporated invacuo to give a orange foam, which was recrystallized from 20 mL of 1:1heptane/i-PrOH to give 6.50 g of compound 3.01 as a light yellow solid.m.p. 176.3 C. ¹H NMR (DMSO-d₆, T=140° C.) δ1.36 (t, J=6.9 Hz, 3H), 1.41(d, J=6.9 Hz, 3H), 1.53 (d, J=19.6 Hz, 1H), 3.18 (br, 1H), 4.12 (q,J=6.9 Hz, 2H), 4.70 (d, J=16.7 Hz, 1H), 4.76 (d, J=16.6 Hz, 1H), 5.28(q, J=6.6 Hz, 1H), 7.08 (br, 3H), 7.15 (dd, J=7.7, 4.8 Hz, 1H), 7.27 (d,J=8.0 Hz, 2H), 7.37 (br, 1H), 7.48-7.58 (m, 4H), 7.68 (d, J=7.7 Hz, 1H),7.85 (m, 1H), 8.10 (m, 1H), 8.34 (d, J=4.5 Hz, 1H), 8.37 (s, 1H) ppm. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 1.83:1 by ¹H NMR (DMSO-d₆, T=25° C.) δ5.11 (q, J=6.8 Hz,1H) & 5.28 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 587.3 [M+H]⁺.

[0277](R)-2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-one hydrochloride (3.01.HCl).

[0278] To a solution of compound 3.01 (3.55 g, 6.05 mmol, 1.0 equiv) in25 mL of ether and 25 mL of dichloromethane was added a 1.0 M solutionof HCl in ether (12.1 mL, 12.1 mmol, 2.0 equiv) dropwise via syringe,followed by another 50 mL of ether. The resulting suspension was stirredat room temperature for 1 h. The precipitates were collected byfiltration. The solids were washed twice with 30 mL of ether and airdried in the dark to give 3.74 g of the product as a white powder. m.p.186.2° C. At room temperature, this compound exists as a mixture ofcis/trans amide rotamers, ca. 1.78:1 by ¹H NMR (DMSO-d₆, T=25° C.) δ1.48(d, J=6.4 Hz, 3H) & 1.22 (d, J=7.2 Hz, 3H) ppm. At 140° C., the ¹H NMRspectra of 3.01.HCl was identical to that of 3.01. MS (ESI⁺) m/z 587.3[M+H]⁺. Chiral HPLC showed the enantiomeric ratio of this product to be98:2 R/S.

Synthesis of Compound 3.02

[0279] The synthesis of compound 3.02 in five steps from commerciallyavailable starting materials provides an example of a3H-quinazolin-4-one synthesis in racemic form. Scheme 4 provides anoverview of the synthetic route, for which the experimental detailsfollow.

[0280] 2-(1-N-BOC-aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-one(XIV).

[0281] To a solution of anthranilic acid (2.74 g, 20 mmol, 1.0 equiv)and N-BOC-D-alanine (3.78 g, 20 mmol, 1.0 equiv) in 20 mL of anhydrouspyridine was added 5.24 mL of triphenylphosphite (6.21 g, 20 mmol, 1.0equiv) at room temperature. The resulting yellow solution was stirred at100° C. for 4 h. 4-Fluoroaniline (2.22 g, 20 mmol, 1.0 equiv) was addedvia syringe. The reaction mixture was stirred for another 3 h at 100°C., cooled to room temperature, and evaporated in vacuo to give a brownresidue. This residue was dissolved in 50 mL of EtOAc. The mixture waswashed successively twice with 40 mL of 5% aqueous phosphoric acid, oncewith 20 mL of saturated NaHCO₃, and once with 40 mL of brine. Theorganic layer was dried over Na₂SO₄ and evaporated in vacuo to give abrown residue, which was purified by silica gel chromatography to give2.40 g of compound XIV as a light yellow solid. ¹H NMR (DMSO-d₆) δ1.22(d, J=6.8 Hz, 3H), 1.31 (s, 9H), 4.21 (m, 1H), 7.30 (m, 1H), 7.42 (m,3H), 7.58 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 8.11(d, J=8.0 Hz, 1H) ppm. MS (ESI⁺) m/z 384.0 [M+H]⁺.

[0282] 2-(1-Aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-onehydrochloride (XV).

[0283] To a solution of compound XIV (2.30 g, 6.0 mmol, 1.0 equiv) in6.0 mL of EtOAc was added 6.0 mL of a 4.0 M solution of HCl in dioxane(24 mmol, 4.0 equiv) at room temperature. After the resulting solutionwas stirred at room temperature for 1.5 h, it was evaporated in vacuo togive a light gray solid. This crude product was dissolved in 9 mL ofdichloromethane. To this stirring solution was added a total of 36 mL ofether via an additional funnel. The precipitates were collected byvacuum filtration, washed twice with 10 mL of ether, and air-dried togive 1.1 g of compound XV as a slightly off-white solid. ¹H NMR(DMSO-d₆) δ1.31 (d, J=6.8 Hz, 3H), 3.89 (m, 1H), 7.20 (t, J=4.8 Hz, 1H),7.48 (m, 2H), 7.67 (m, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.95 (t, J=7.6 Hz,1H), 8.18 (d, J=8.0 Hz, 1H), 8.53 (br, 3H) ppm. MS (ESI⁺) m/z 284.0[M+H]⁺.

[0284]2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-one(3.02).

[0285] 3-Picolylchloride hydrochloride (333 mg, 2.03 mmol, 1.15 equiv),KI (59 mg, 0.35 mmol, 0.20 equiv), compound XV (0.56 g, 1.77 mmol, 1.0equiv), and K₂CO₃ (513 mg, 3.71 mmol, 2.1 equiv) were added to 2.5 mL ofDMF. The mixture was vigorously stirred for 14 h at room temperature.The mixture was poured into 20 mL of 10% Na₂CO₃ and extracted four timeswith 10 mL of EtOAc. The combined EtOAc extract was washed once with 20mL of brine, dried over Na₂SO₄, and evaporated in vacuo to give anorange colored foam, which was used without further purification.

[0286] To the above crude product was added4-trifluoromethylphenylacetic acid (542 mg, 2.66 mmol, 1.5 equiv), EDC(594 mg, 3.10 mmol, 1.75 equiv) HOBT (419 mg, 3.00 mmol, 1.7 equiv),N-methylmorpholine (304 mg, 3.00 mmol, 1.7 equiv), and 6.0 mL ofdichloromethane at room temperature. The mixture was stirred at roomtemperature for 14 h. The reaction mixture was poured into a 20 mL of10% citric acid, and extracted twice with 15 mL of EtOAc. The combinedEtOAc extract was washed once with 20 mL of saturated NaHCO₃, and oncewith 20 mL of brine. The organic layer was dried over Na₂SO₄ andevaporated in vacuo to give a brown residue, which was purified bysilica gel chromatography to give 169 mg of compound 3.02 as a whitesolid. m.p. 167.0° C. ¹H NMR (DMSO-d₆, T=140° C.) δ1.40 (d, J=6.7 Hz,3H), 3.32 (br, 1H), 3.59 (d, J=15.8 Hz, 1H), 4.73 (d, J=17.6 Hz, 1H),4.81 (d, J=17.2 Hz, 1H), 5.26 (q, J=6.5 Hz, 1H), 7.18 (dd, J=7.7 Hz, 4.8Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.34 (m, 3H), 7.55 (m, 5H), 7.67 (d,J=8.0 Hz, 1H), 7.86 (dd, J=7.6, 1.6 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H),8.36 (d, J=4.8 Hz, 1H), 8.40 (s, 1H) ppm. At room temperature, thiscompound exists as a mixture of cis/trans amide rotamers, ca. 0.96:1molar ratio (DMSO-d₆, T=25° C.) d 5.10 (q, J=6.8 Hz, 1H) & 5.31 (q,J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 561.2 [M+H]⁺. Chiral HPLC showed theenantiomeric ratio of this product to be ca. 1:1 R/S.

[0287]2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-onehydrochloride (3.02.HCl).

[0288] To a solution of compound 3.02 (50 mg, 89 μmol, 1.0 equiv) in 2mL of dichloromethane was added a 1.0 M solution of HCl in ether (180μL, 0.18 mmol, 2.0 equiv) dropwise via syringe, followed by another 5 mLof ether. The resulting suspension was stirred at room temperature for 1h. The precipitates were collected by filtration. The solids were washedtwice with 30 mL of ether and air dried in the dark to give 47 mg of theproduct as a white powder. mp 122.7° C. At room temperature, thiscompound exists as a mixture of cis/trans amide rotamers, ca. 0.93:1 by¹H NMR (DMSO-d₆, T=25° C.) δ5.05 (q, J=6.8 Hz, 1H) & 5.18 (q, J=6.8 Hz,1H) ppm. MS (ESI⁺) m/z 561.2 [M+H]⁺.

Synthesis of Compound 3.03 and Compound 3.03.HCl

[0289]

[0290] The synthesis of compound 3.03 followed the method described forcompound 3.02. 2-Picolylchloride hydrochloride was used in place of3-picolylchloride hydrochloride in step 3 of the synthetic sequence.Characterization of the products follows.

[0291]2-((N-(2-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-one(3.03) was obtained as a white solid from compound XV. Mp 159.2° C. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.23:1 by ¹H NMR (DMSO-d₆, T=25° C.) δ5.05 (q, J=6.8 Hz,1H) & 5.36 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 561.2 [M+H]⁺.

[0292]2-((N-2-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-fluorophenyl)-3H-quinazoline-4-onehydrochloride (3.03.HCl) was obtained as a white solid from compound3.03. At room temperature, this compound exists as a mixture ofcis/trans amide rotamers, ca. 0.64:1 by ¹H NMR (DMSO-d₆, T=25° C.) δ5.04(q, J=6.8 Hz, 1H) & 5.35 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 561.2[M+H]⁺.

Synthesis of Compounds 3.04 and 3.04.HCl

[0293]

[0294] The synthesis of compound 3.04 followed the method described forcompound 3.02. p-Phenetidine was used in place of 4-fluoroaniline instep 1 of the synthetic sequence. 2-Picolylchloride hydrochloride wasused in place of 3-picolylchloride hydrochloride in step 3 of thesynthetic sequence. Characterization of the products follows.

[0295]2-((N-2-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-one(3.04) was obtained as a white solid from the hydrochloride salt ofracemic compound XIII. Mp 167.5 C. ¹H NMR (DMSO-d₆, T=140° C.) δ1.35 (d,J=6.9 Hz, 3H), 1.37 (t, J=7.4 Hz, 3H), 3.49 (br, 1H), 3.64 (m, 1H), 4.10(q, J=9.1 Hz, 2H), 4.78 (d, J=17.2 Hz, 1H), 4.84 (d, J=17.2 Hz, 1H),5.38 (q, J=6.2 Hz, 1H), 7.02 (br, 2H), 7.09 (dd, J=6.7, 4.8 Hz, 1H),7.18 (d, J=7.9 Hz, 1H), 7.30 (m, 4H), 7.46-7.58 m, 4H), 7.61 (d, J=8.3Hz, 1H), 7.79 (m, 1H), 8.07 (dd, J=8.0, 1.4 Hz, 1H), 8.36 (m, 1H) ppm.At room temperature, this compound exists as a mixture of cis/transamide rotamers, ca. 0.42:1 molar ratio (DMSO-d₆, T=25° C.) d 5.12 (q,J=6.8 Hz, 1H) & 5.34 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 587.2 [M+H]⁺.

[0296]2-((N-(2-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethoxyphenyl)-3H-quinazoline-4-onehydrochloride (3.04-HCl) was obtained as a white solid from compound3.04. Mp 162.6° C. At room temperature, this compound exists as amixture of cis/trans amide rotamers, ca. 1.45:1 molar ratio (DMSO-d₆,T=25 ° C.) d 1.51 (d, J=6.4 Hz, 1H) & 1.24 (d, J=7.2 Hz, 1H) ppm. MS(ESI⁺) m/z 587.2 [M+H]⁺.

Synthesis of Compound 3.05

[0297] The synthesis of compound 3.05 is closely related to that ofcompound 3.02 described above. Scheme 5 provides an overview ofsynthetic route. Compound 3.05 also served as a common precursor for aseries of closely related compounds.

[0298] 2-(1-Aminoethyl)-3-(4-iodophenyl)-3H-quinazoline-4-onehydrochloride (XVI)

[0299] The product was a white solid. ¹H NMR (DMSO-d₆) δ1.31 (d, J=6.8Hz, 3H), 3.89 (m, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H),7.63 (t, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.97 (m, 3H), 8.14 (d,J=8.0 Hz, 1H), 8.51 (br, 3H) ppm. MS (ESI⁺) m/z 392.0 [M+H]⁺.

[0300]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-iodophenyl)-3H-quinazoline-4-one(3.05) was obtained as a white solid from compound XVI. Mp 181.8° C. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.64:1 by ¹H NMR (DMSO-d₆, T=25° C.) δ4.89 (q, J=6.0 Hz,1H) & 5.22 (q, J=6.4 Hz, 1H) ppm. MS (ESI⁺) m/z 650.2 [M+H]⁺.

[0301]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-cyanophenyl)-3H-quinazoline-4-one(3.06).

[0302] 3.05 (150 mg, 0.23 mmol, 1.0 equiv) was dissolved in 0.5 mL ofanhydrous DMF. CuCN (31 mg, 0.35 mmol, 1.5 equiv) was added. Theresulting mixture was heated to 130° C. for 16 h. The mixture was cooledto room temperature and diluted with 15 mL of EtOAc. The mixture wasfiltered through a short column of silica gel, which was further elutedwith 50 mL of EtOAc. The eluent was concentrated in vacuo to give ayellow residue, which was purified by preparative TLC to give 95 mg ofcompound 3.06 as a white solid. Mp 197.0° C. ¹H NMR (DMSO-d₆, T=140° C.)δ0.98 (t, J=6.9 Hz, 3H), 1.44 (d, J=6.8 Hz, 3H), 3.30-3.65 m, 8H), 5.16(q, J=6.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.50-7.77 (m, 6H), 7.72-7.95(m, 3H), 8.15 (dd, J=7.9, 1.5 Hz, 1H) ppm. At room temperature, thiscompound exists as a mixture of cis/trans amide rotamers, ca. 0.64:1molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C.) δ4.84 (q, J=6.4 Hz, 1H)& 5.22 (q, J=6.4 Hz, 1H) ppm. MS (ESI⁺) m/z 650.2 [M+H]⁺.

[0303]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-trimethylsilylethynylphenyl)-3H-quinazoline-4-one(3.07).

[0304] Compound 3.05 (150 mg, 0.23 mmol, 1.0 equiv) was dissolved in 1.0mL of anhydrous THF. Trimethylsilylacetylene (45 mg, 0.46 mmol, 2.0equiv), CuI (87 mg, 0.46 mmol, 2.0 equiv), Pd(PPh₃)₂Cl₂ (32 mg, 0.046mmol, 0.20 equiv), and triethylamine (92 mg, 0.91 mmol, 4.0 equiv) wereadded sequentially. The resulting mixture was heated to 50° C. for 3 h.The mixture was cooled to room temperature and diluted with 15 mL ofEtOAc. The mixture was filtered through a short column of silica gel,which was further eluted with 50 mL of EtOAc. The eluent wasconcentrated in vacuo to give a yellow residue, which was purified bypreparative TLC to give 105 mg 3.07 as a white solid. Mp 185.3° C. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.54:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C.)δ4.88 (q, J=6.8 Hz, 1H) & 5.25 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z620.2 [M+H]⁺.

[0305]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethynylphenyl)-3H-quinazoline-4-one(3.08).

[0306] Compound 3.07 (57 mg, 92 μmol, 1.0 equiv) was dissolved in 1.0 mLof anhydrous THF. A 1.0 M solution of tetrabutylammonium fluoride in THF(101 μL, 0.101 mmol, 1.1 equiv) was added at room temperature. Theresulting mixture was stirred at room temperature for 15 min. To thereaction mixture was added 100 μL of saturated aqueous NH₄Cl and 15 mLof EtOAc. After stirring at room temperature for another 15 min, themixture was dried over Na2SO4, and filtered through a short column ofsilica gel, which was further eluted with 50 mL of EtOAc. The eluent wasconcentrated in vacuo to give a yellow residue, which was purified bypreparative TLC to give 39 mg of compound 3.08 as a white solid. Mp186.7° C. At room temperature, this compound exists as a mixture ofcis/trans amide rotamers, ca. 0.54:1 molar ratio in DMSO. ¹H NMR(DMSO-d₆, T=25° C.) δ4.87 (q, J=6.0 Hz, 1H) & 5.20 (q, J=6.8 Hz, 1H)ppm. MS (ESI⁺) m/z 548.2 [M+H]⁺.

Synthesis of Compounds 3.09 and 3.10

[0307]

[0308] Compounds 3.09 and 3.10 were synthesized in the same manner ascompound 3.07 (See Scheme 7). 3,3-Dimethyl-1-butyne, and2-methyl-3-butyn-2-ol were used respectively, instead oftrimethylsilylacetylene. Characterization of the products follows.

[0309]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-(t-butylethynyl)phenyl)-3H-quinazoline-4-one(3.09) was obtained from compound 3.05 in as a white solid. Mp 189.9° C.At room temperature, this compound exists as a mixture of cis/transamide rotamers, ca. 0.69:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25°C.) δ4.89 (q, J=6.4 Hz, 1H) & 5.25 (q, J=6.4 Hz, 1H) ppm. MS (ESI⁺) m/z604.2 [M+H]⁺.

[0310]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-(3-hydroxy-3-methyl-1-butynyl)phenyl)-3H-quinazoline-4-one(3.10) was obtained from compound 3.05 as a white solid. Mp 162.2° C. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.69:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C.)δ4.89 (q, J=6.8 Hz, 1H) & 5.24 (q, J=6.4 Hz, 1H) ppm. MS (ESI⁺) m/z606.3 [M+H]⁺.

Synthesis of Compounds 3.11 and 3.12

[0311]

[0312] Compounds 3.11 and 3.12 were synthesized in the same manner ascompounds 3.07 and 3.08 (Scheme 7). Compound 1.42 was used as startingmaterial in both cases, instead of compound 3.05. Characterization ofthe products follows.

[0313]2-((N-2-Methoxyethyl)-N-(4-phenylphenylacetyl)-1-aminoethyl)-3-(4-trimethylsilylethynyl)phenyl)-3H-quinazoline-4-one(3.11) was obtained from compound 1.42 as a white solid. At roomtemperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.61:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C.)δ4.91 (q, J=6.4 Hz, 1H) & 5.21 (q, J=6.4 Hz, 1H) ppm. MS (ESI⁺) m/z614.3 [M+H]⁺.

[0314]2-((N-2-Methoxyethyl)-N-(4-phenylphenylacetyl)-1-aminoethyl)-3-(4-ethynylphenyl)-3H-quinazoline-4-one(3.12) was obtained from compound 1.42 as a white solid. Mp 73.3° C. Atroom temperature, this compound exists as a mixture of cis/trans amiderotamers, ca. 0.67:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C)δ4.92 (q, J=6.4 Hz, 1H) & 5.17 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z542.2 [M+H]⁺.

[0315] Synthesis of Compounds 3.13 and 3.14.

[0316] Compounds 3.13 and 3.14 were synthesized in the same reactionfrom compound 3.05. Experimental details follow.

[0317]2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-phenyl-3H-quinazoline-4-one(3.13) and2-((N-2-Ethoxyethyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-ethylphenyl)-3H-quinazoline-4-one(3.14)

[0318] To a solution of compound 3.05 (98 mg, 0.15 mmol, 1.0 equiv) andPd(PPh₃)₄ (35 mg, 30 μmol, 0.20 equiv) in 1.0 mL of THF was added Et₂Zn(37 mg, 0.30 mmol, 2.0 equiv) via syringe. The darkened reaction mixturewas stirred at 50° C. for 3 h. After cooling to room temperature, thereaction mixture was diluted with 20 mL of EtOAc, and washedsuccessively with 10 mL of 1 M HCl, 10 mL of saturated NaHCO₃, and 10 mLof brine. The organic layer was dried over Na2SO4, and evaporated invacuo to give a brown residue, which was purified by preparative TLC togive 18 mg of compound 3.13 and 27 mg of compound 3.14. Both are whitesolids. Characterization of these two products follows.

[0319] Compound 3.13.

[0320] At room temperature, this compound exists as a mixture ofcis/trans amide rotamers, ca. 0.69:1 molar ratio in CDCl₃. ¹H NMR(CDCl₃, T=25° C.) δ0.71 (d, J=7.0 Hz, 3H) & 1.15 (d, J=7.0 Hz, 1H) ppm.MS (ESI⁺) m/z 524.3 [M+H]⁺.

[0321] Compound 3.14.

[0322] At room temperature, this compound exists as a mixture ofcis/trans amide rotamers, ca. 0.69:1 molar ratio in CDCl₃. ¹H NMR(CDCl₃, T=25° C.) δ4.88 (q, J=6.8 Hz, 1H) & 5.34 (q, J=6.8 Hz, 1H) ppm.MS (ESI⁺) m/z 552.2 [M+H]⁺.

Synthesis of Compound 3.15

[0323]

[0324] Compound 3.15 was synthesized from compound 1.42 using Pdcatalyzed hydrogenation. Experimental details follow.

[0325]2-((N-2-Methoxyethyl)-N-(4-phenylphenylacetyl)-1-aminoethyl)-3-phenyl-3H-quinazoline-4-one(3.15)

[0326] To a solution of compound 1.42 (25 mg, 39 μmol, 1.0 equiv) in amixture of 1.0 mL of MeOH and 1.0 mL of dichloromethane, was added 10%Pd on carbon (83 mg, 78 μmol, 2.0 equiv). Excess hydrogen was introducedusing a balloon. After stirring at room temperature for 2 h. Thereaction mixture was diluted with 5 mL of dichloromethane, and filteredthrough a pad of Celite. The filtrate was concentrated in vacuo to givea yellow oil, which was passed through a short column of silica gel,eluted with EtOAc. The eluent was concentrated in vacuo to give 17 mg ofcompound 3.15 as a colorless oil. At room temperature, this compoundexists as a mixture of cis/trans amide rotamers, ca. 1.06:1 molar ratioin DMSO. ¹H NMR (DMSO-d₆, T=25° C.) δ4.94 (q, J=6.4 Hz, 1H) & 5.08 (q,J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 518.3 [M+H]⁺.

[0327] Synthesis of Compound 3.16

[0328] Compound 3.16 was synthesized from the racemic form of compoundXII as described in the experimental details below.

[0329]2-((N-3-Picolyl)-N-(t-butoxycarbonyl)-1-aminoethyl)-3-(4-5-ethoxyphenyl)-3H-quinazoline-4-one(3.16).

[0330] To a solution of racemic compound XII (124 mg, 0.30 mmol, 1.0equiv) in 0.60 mL of DMF, was added 3-picolylchloride hydrochloride (55mg, 0.33 mmol, 1.1 equiv), KI (50 mg, 0.30 mmol, 1.0 equiv), and NaH(60% suspension in mineral oil, 25 mg, 0.62 mmol, 2.05 equiv). Afterstirred at room temperature for 16 h, the reaction mixture was pouredinto 10 mL of 5% aqueous 10H₃PO₄. The resulting mixture was extractedtwice with 10 mL of EtOAc. The organic layer was washed with 10 mL ofNaHCO₃ and 10 mL of brine, dried over Na₂SO₄ and concentrated in vacuoto give a yellow oil, which was purified by preparative TLC to give 33mg of compound 3.16 as a white solid. Mp 67.5° C. At room temperature,this compound exists as a mixture of cis/trans amide rotamers, ca.1.11:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆, T=25° C.) δ5.03 (m, 1H) &5.12 (m, 1H) ppm. MS (ESI⁺) m/z 510.3 [M+H]⁺.

[0331] Synthesis of Compound 3.16a

[0332](1-N-BOC-aminoethyl)-3-(4-ethoxyphenyl)-2-{(1R)-1-[(pyridin-3-ylmethyl)-amino]-ethyl}-3H-pyrido[2,3-d]pyrimidin-4-one(XVII precursor).

[0333] To a 3 L round bottom flask equipped with addition funnel,mechanical stirrer and temperature probe was added 102.60 g (542.26mmol) of N-(tert-butoxycarbonyl)-D-alanine in 1.2 L of dichloromethane(DCM) under a nitrogen atmosphere. The solution was cooled to −20° C.and 150.00 ml (1364.31 mmol) of N-methyl morpholine added followed bythe addition of a solution containing 140.1 ml (1084 mmol) ofiso-butylchloroformate in 360 ml of DCM over 40 min. while maintainingthe reaction temperature below −20° C. After complete addition, thereaction was allowed to stir for 45 min. and 75.00 g (542.97 mmol) of2-aminonicotinic acid added. The reaction was allowed to warm to roomtemperature overnight. The reaction was diluted with 1.5 L DCM andwashed with 1.0 N hydrochloric acid (2×750 ml) and brine (1×500 ml). Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 175.0 g of a yellow-orange oil. Thematerial was used without further purification in the next step.

[0334] A solution containing the crude material from above dissolved in2 L DCM was cooled to −20° C. under a nitrogen atmosphere and 69.00 ml(535.68 mmol) of p-phenetidine was added over 5 minutes. After stirringwith gradual warming to 0° C. the reaction mixture was transferred to aseparatory funnel and washed with 1.0 N hydrochloric acid (2×500 ml),saturated sodium bicarbonate solution (2×1 L), and brine (1×1 L). Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 175.2 g of crude bis-amide. The materialwas used without further purification in the next step.

[0335] A solution containing the crude bis-amide prepared above in 2.3 Lof DCM and 50.0 ml (454.7 mmol) of N-methyl morpholine was cooled to−20° C. under a nitrogen atmosphere and 53.0 ml (408.6 mmol) ofiso-butylchloroformate was added dropwise over a period of 5 minutes.Upon completed addition of the chloroformate HPLC analysis indicated nobis-amide remained. The reaction mixture was transferred to a separatoryfunnel and washed with 1.0 N hydrochloric acid (2×1 L), saturatedbicarbonate solution (1×1 L), and brine (1×1 L). The organic phase wasdried over magnesium sulfate, filtered, and concentrated in vacuo togive 205 g of a brown, viscous oil. This product was dissolved in 500 mlof methyl tert-butyl ether and allowed to stir until the product beganto precipitate from the solution. Heptane was then added (1000 ml) andstirring continued. The resulting precipitate was collected byfiltration, washed with heptane, and dried to afford 78.9 g of productas an off-white solid. ¹H NMR (CDCl₃) δ8.99 (dd, J₁=2.0 Hz, J₂=4.4 Hz,1H), 8.60 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H), 7.44 (dd, J₁=4.4 Hz, J₂=8.0Hz, 1H), 7.33 (dd, J₁=1.6 Hz, J₂=8.8 Hz, 1H), 7.16 (dd, J₁=2.8 Hz,J₂=8.8 Hz, 1H), 7.20 (dd, J₁=2.4 Hz, J₂=8.8 Hz, 1H), 7.04 (dd, J₁=2.8Hz, J₂=8.8 Hz, 1H), 5.80 (d, J=8.8 Hz, 1H), 4.63-4.70 (m, 1H), 4.06-4.13(q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H), 1.40 (s, 9H), 1.31 (d, J=6.8Hz, 3H) ppm.

[0336] Intermediate XVII.

[0337] To a solution containing 77.00 g (187.59 mmol) of the compoundprepared above in 2.1 L of DCM was added 290 mL trifluoroacetic acid.The reaction was allowed to stir for 3.5 h at room temperature thenconcentrated in vacuo. The concentrate was dissolved in 1.4 L DCM andwashed with 1.0 N hydrochloric acid (3×500 ml). The combined aqueouswashes were made alkaline by addition of concentrated ammonium hydroxideuntil pH=10. The resulting cloudy solution was extracted with DCM (2×700ml) and the combined organic extracts dried over magnesium sulfate,filtered, and concentrated in vacuo to afford 58.40 g of product as atan solid. ¹H NMR (DMSO-d₆) δ8.94 (dd, J₁=2.0 Hz, J₂=4.8 Hz, 1H), 8.44(dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H), 7.49 (dd, J₁=4.8 Hz, J₂=8.0 Hz, 1H),7.34-7.39 (m, 2H), 7.04-7.10 (m, 2H), 4.08 (q, J=6.8 Hz, 2H), 3.52 (q,J=6.4 Hz, 1H), 1.94 (br s, 2H), 1.34 (t, J=6.8 Hz, 3H), 1.15 (d, J=6.4Hz, 3H) ppm.

[0338] Intermediate XVIII.

[0339] To a solution containing 57.70 g (185.92 mmol) of intermediateXVII prepared above dissolved in 1.7 L of dichloroethane was added 18.5ml (196.04 mmol) pyridine carboxaldehyde followed by 55.20 g (260.45mmol) of sodium triacetoxy borohydride. The reaction was allowed to stirat room temperature overnight. The reaction was diluted with 1 L of DCMand washed with 1.0 M ammonium hydroxide (2×500 ml). The organic phasewas dried over magnesium sulfate, filtered, and concentrated in vacuo toafford 79.20 g of product as a pale yellow solid. ¹H NMR (DMSO-d₆)δ8.96-8.98 (m, 1H), 8.42-8.48 (m, 1H), 8.45 (br s, 1H), 8.37 (d, J=4.8Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.52 (dd, J₁=4.8 Hz, J₂=8.0 Hz, 1H),7.33 (dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 7.24 (dd, J₁=4.8 Hz, J₂=8.0 Hz,1H), 7.14 (dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 6.99 (dd, J₁=2.8 Hz, J₂=8.4Hz, 1H), 6.83 (dd, J₁=2.8 Hz, J₂=8.8 Hz, 1H), 3.97-4.10 (m, 1H), 3.87(s, 1H), 3.72 (d, J=14.0 Hz, 1H), 3.52 (d, J=13.6 Hz, 1H), 3.28 (q,J=6.4 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H), 1.17 (d, J=6.4 Hz, 3H) ppm.

[0340] Compound 3.16a.

[0341] To a solution containing 54.00 g (245.29 mmol) of4-(trifluoromethoxy) phenylacetic acid in 1.1 L of DMF was added 61.30 g(319.77 mmol) of EDCI, 43.20 g (319.69 mmol) HOBT and 42.00 ml (382.01mmol) of N-methyl morpholine. After stirring for 30 min., 74.60 g(185.82 mmol) of intermediate XVIII was added. The reaction was allowedto stir at room temperature overnight. The reaction was diluted with 3 LDCM and washed with water (2×3 L), saturated sodium bicarbonate solution(2×2 L), and brine (1×2 L). The organic extract was dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford 121.7 g of ayellow solid. The solids were triturated with 700 ml of methyltert-butyl ether, collected by filtration, rinsed, and dried to afford88.46 g of product as an off-white solid.

[0342] The product was recrystallized from 10% ethyl acetate in heptaneto afford a colorless, microcrystalline (small needles) solid, m.p.161.2° C. ¹H NMR (T=120° C.; DMSO-d₆) δ9.01 (dd, J₁=1.6 Hz, J₂=4.4 Hz,1H), 8.46 (dd, J₁=2.0 Hz, J₂=7.6 Hz, 1H), 8.35 (m, 2H), 7.57 (dd, J₁=4.8Hz, J₂=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H),7.06-7.22 (m, 7H), 5.28 (q, J=6.0 Hz, 1H), 4.76 (br s, 2H), 4.13 (q,J=6.8 Hz, 2H), 3.48 (br s, 0.5-1H [H₂O]), 2.91 (br s, 2H), 1.42 (d,J=6.8 Hz, 3H), 1.36 (t, J=6.8 Hz, 3H), ppm. HPLC>99%, chiral HPLC>96%ee). MS (ESI, positive mode): 626 (MH⁺).

[0343] Synthesis of Compound 3.16b

[0344] Compound 3.16b was prepared following the synthetic procedure forcompound 3.16a, wherein 3-trifluoromethyl-4-fluorophenylacetic acid wasused instead of 4-(trifluoromethoxy)phenylacetic acid.

Synthesis of Compound 3.17

[0345]

[0346] Compound 3.17 was prepared following the synthesis of compound3.01 described above. Example 3.02 was followed for the syntheticsequence, wherein 2-aminonicotinic acid was used in step a instead of2-aminobenzoic acid. Characterization data for compound 3.17 follows:colorless, viscous oil. ¹H NMR similar to spectrum for compound 3.01: amixture of cis/trans amide rotamers in ca. 2:1 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 5.16 (q, 1.0H, J=6.8 Hz) andδ_(major) 5.40 (q, 2.0H, J=7.2 Hz) ppm. MS (ESI⁺) 588.2 [MH]⁺

Synthesis of Compound 3.17a

[0347]

[0348] Compound 3.17a was prepared following the synthetic procedure forcompound 3.17, wherein 4-trifluoromethylbenzenamine was used instead ofp-phenetidine.

Synthesis of Compound 3.18

[0349]

[0350] Compound 3.18 was prepared following the synthesis of compound3.01 described above. Example 3.02 was followed for the syntheticsequence, wherein 2-aminonicotinic acid was used in step a instead of2-aminobenzoic acid, and 2-bromoethyl ethyl ether was used in step cinstead of 3-picolyl chloride. Characterization data for compound 3.18follows: colorless, viscous oil. ¹H NMR similar to spectrum for compound3.01: a mixture of cis/trans amide rotamers in ca. 3:2 (CDCl₃; T=25° C.)characteristic resonance peaks at δ_(minor) 5.00 (q, 1.0H, J=6.4 Hz) andδ_(major) 5.00 (q, 1.5H, J=6.8 Hz) ppm. MS (ESI⁺) 569.3 [MH]⁺

Synthesis of Compound 3.19

[0351]

[0352] Compound 3.19 was prepared following the synthesis of compound3.01 described above. Example 3.02 was followed for the syntheticsequence, wherein 2-aminonicotinic acid and 4-cyanoanilne were used instep a instead of 2-aminobenzoic acid and 4-ethoxyaniline, andimidazole-2-carboxaldehyde was used in step c via reductive aminationinstead of 3-picolyl chloride via amine alkylation. Characterizationdata for compound 3.19 follows: colorless, viscous oil. ¹H NMR singleamide rotamer (CDCl₃; T=25° C.) δ1.45 (d, 3H, J=7.6 Hz), 3.69 (d, 1H,J=15.2 Hz), 3.79 (d, 1H, J=15.2 Hz), 4.74 (q, 1H, J=7.2 Hz), 4.76 (d,1H, J=19.6 Hz), 5.39 (d, 1H, J=19.6 Hz), 7.02 (t, 1H, J=1.6 Hz), 7.07(d, 1H, J=2.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 7.40 (d, 2H, J=8.0 Hz), 7.47(dd, 1H, J₁=2.0 Hz, J₂=8.4 Hz), 7.60 (dd, 1H, J₁=4.8 Hz, J₂=8.0 Hz),7.95 (dd, 1H, J₁=2.0 Hz, J₂=6.8 Hz), 8.00 (dd, 1H, J₁=2.0 Hz, J₂=8.4Hz), 8.11 (dd, 1H, J₁=2.0 Hz, J₂=8.4 Hz), 8.66 (dd, 1H, J₁=1.6 Hz,J₂=7.6 Hz), 9.04 (dd, 1H, J₁=1.6 Hz, J₂=4.4 Hz) ppm. MS (ESI⁺) 569.3[MH]⁺

Synthesis of Compound 3.20

[0353]

[0354] Compound 3.20 was prepared following the synthesis of compound3.01 described above. Example 3.02 was followed for the syntheticsequence, wherein 2-aminonicotinic acid and 4-cyanoaniline were used instep a instead of 2-aminobenzoic acid and 4-ethoxyaniline, and3-pyridinecarboxaldehyde was used in step c via reductive aminationinstead of 3-picolyl chloride via amine alkylation. Characterizationdata for compound 3.20 follows: colorless, viscous oil. ¹H NMR singleamide rotamer (CDCl₃; T=25° C.) δ1.33 (d, 3H, J=7.2 Hz), 3.66 (d, 1H,J=15.6 Hz), 3.79 (d, 1H, J=15.6 Hz), 5.16 (d, 1H, J=18.0 Hz), 5.19 (q,1H, J=7.2 Hz), 5.24 (d, 1H, J=18.0 Hz), 7.23-7.32 (m, 3H), 7.45 (dd, 1H,J₁=1.6 Hz, J₂=8.0 Hz), 7.49-7.55 (m, 4H), 7.89 (dd, 1H, J₁=1.6 Hz,J₂=8.4 Hz), 7.95 (dd, 1H, J₁=1.2 Hz, J₂=8.0 Hz), 8.02 (dd, 1H, J₁=2.0Hz, J₂=8.4 Hz), 8.52-8.58 (m, 2H), 8.62 (dd, 1H, J₁=2.0 Hz, J₂=8.0 Hz),9.07 (dd, 1H, J₁=2.0 Hz, J₂=4.8 Hz) ppm. MS (ESI⁺) 569.2 [MH]⁺

Synthesis of Compound 3.21

[0355]

[0356] Compound 3.21 was prepared following the synthesis of compound3.01 described above. Example 3.02 was followed for the syntheticsequence, wherein 2-aminonicotinic acid and 4-cyanoaniline were used instep a instead of 2-aminobenzoic acid and 4-ethoxyaniline, and3-methyl-4-carboxaldehyde-(3H)imidazole was used in step c via reductiveamination instead of 3-picolyl chloride via amine alkylation.Characterization data for compound 3.21 follows: colorless, viscous oil.¹H NMR single amide rotamer (CDCl₃; T=25° C.) δ1.41 (d, 3H, J=7.2 Hz),3.66 (s, 3H), 3.75 (d, 1H, J=16.0 Hz), 3.84 (d, 1H, J=16.0 Hz), 4.98 (s,2H), 5.17 (q, 1H, J=7.2 Hz), 6.86 (s, 1H), 7.30 (s, 1H), 7.40-7.50 (m,3H), 7.50-7.58 (m, 3H), 7.80-8.05 (m, 3H), 8.63 (dd, 1H, J₁=2.0 Hz,J₂=8.0 Hz), 9.06 (dd, 1H, J₁=2.0 Hz, J₂=4.4 Hz) ppm. MS (ESI⁺) 572.2[MH]⁺

Synthesis of Compound 3.22

[0357]

[0358] Compound 3.22 was prepared following the synthetic procedure forcompound 3.02, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.13 (d,J=8.1 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.65-7.45(m, 5H), 7.40-7.20 (m, 4H), 5.30 (bs, 1H), 4.40 (bs, 2H), 3.40 (bs, 2H),1.99 (s, 3H), 1.34 (d, J=6.6 Hz, 3H). m.p. 220-221° C. MS (ESI⁺) 526.2[MH]⁺.

Synthesis of Compound 3.23

[0359]

[0360] A mixture of compound 3.22 (11 mg, 0.021 mmol) and methoxylaminehydrochloride (0.08 mL, 25-30% aqueous solution) in methanol (4 mL) andpyridine (0.1 mL) was stirred at room temperature for three days. Thesolvents were evaporated, and the residue was purified by column (30%EtOAc in Hexane) to give 12 mg of 3.23 as white solid. MS (ESI⁺) 555.2[MH]⁺.

Synthesis of Compound 3.24

[0361]

[0362] Compound 3.24 was prepared following the synthetic procedure forcompound 3.23, described above. MS (ESI⁺) 541.3 [MH]⁺.

Synthesis of Compound 3.25

[0363]

[0364] Compound 3.25 was prepared following the synthetic procedure forcompound 3.02, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.14 (d,J=8.1 Hz, 1H), 7.84 (m, 2H), 7.74 (m, 3H), 7.55 (t, J=8.2 Hz, 1H), 7.30(m, 2H), 7.00 (m, 2H), 5.20 (q, J=6.9 Hz, 1H), 4.05 (dd, J=6.9, 7.0 Hz,2H), 3.80-3.25 (m, 8H), 1.49 (d, J=6.9 Hz, 3H), 1.31 (t, J=7.0 Hz, 3H),0.95 (t, J=7.0 Hz, 3H). m.p. 57-60° C. MS (ESI⁺) 636.2 [MH]⁺. Anal.Calcd. for C₃₂H₃₁F₆N₃O₄: C, 60.47; H, 4.92; N, 6.61. Found: C, 60.36; H,4.99; N, 6.51.

Synthesis of Compound 3.26

[0365]

[0366] Compound 3.26 was prepared following the synthetic procedure forcompound 3.02, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.13 (d,J=8.0 Hz, 1H), 7.84 (t, J=8.1 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.54 (t,J=8.2 Hz, 1H), 7.42 (m, 2H), 7.28-7.19 (m, 3H), 7.15 (m, 2H), 5.15 (q,J=6.8 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.65-3.20 (m, 8H), 1.46 (d, J=6.8Hz, 3H), 1.34 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.0 Hz, 3H). m.p. 137-138°C. MS (ESI⁺) 586.2 [MH]⁺. Anal. Calcd. for C₃₁H₃₁F₄N₃O₄: C, 63.58; H,5.34; N, 7.18. Found: C, 63.47; H, 5.45; N, 7.40.

Synthesis of Compound 3.27

[0367]

[0368] Compound 3.27 was prepared following the synthetic procedure forcompound 3.02, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.13 (d,J=8.0 Hz, 1H), 7.84 (t, J=8.1 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.57 (m,2H), 7.40-7.20 (m, 2H), 7.13 (m, 1H), 7.05 (m, 2H), 6.84 (d, J=8.8 Hz,1H), 5.17 (q, J=6.9 Hz, 2H), 4.09 (q, J=7.0 Hz, 2H), 3.65-3.20 (m, 8H),1.46 (d, J=6.8 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.0 Hz, 3H).m.p. 146-148° C. MS (ESI⁺) 586.2 [MH]⁺. Anal. Calcd. for C₃₁H₃₁F₄N₃O₄:C, 63.58; H, 5.34; N, 7.18. Found: C, 63.76; H, 5.43; N, 7.19.

Synthesis of Compound 3.28

[0369]

[0370] Compound 3.28 was prepared following the synthetic procedure forcompound 3.02, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.33 (m,2H), 8.09 (d, J=8.1 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz,1H), 7.54 (t, J=8.1 Hz, 1H), 7.48 (m, 1H), 7.36 (m, 1H), 7.18-7.04 (m,4H), 7.01 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 5.25 (q, J=6.8 Hz,2H), 4.70 (s, 2H), 4.60 (q, J=8.9 Hz, 2H), 4.14 (q, J=7.0 Hz, 2H),3.35-3.00 (bm, 2H), 1.37 (m, 6H). m.p. 103-104° C. MS (ESI⁺) 617.3[MH]⁺. Anal. Calcd. for 2H), 4.70 (s, 2H), 4.60 (q, J=8.9 Hz, 2H), 4.14(q, J=7.0 Hz, 2H), 3.35-3.00 (bm, 2H), 1.37 (m, 6H). m.p. 103-104° C. MS(ESI⁺) 617.3 [MH]⁺. Anal. Calcd. for C₃₄H₃₁F₃N₄041/2H₂O: C, 65.27; H,5.16; N, 8.96. Found: C, 65.01; H, 5.12; N, 8.96.

Synthesis of Compound 3.29

[0371]

[0372] Compound 3.29 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, ¹H NMR (DMSO, T=140° C.) 1.35 (t, 3H,J=6.8 Hz ), 1.50 (d, 3H, J=6.8 Hz), 3.58 (m, 2H), 4.10 (q, 2H, J=6.8Hz), 4.50 (m, 2H), 5.23 (q, 1H, J=6.8 Hz), 7.11 (m, 2H), 7.29-7.62 (m,6H), 7.78 (m, 2H), 7.88 (t, 1H, J=8 Hz), 8.15 (dd, 1H, J₁=1.2 Hz, J₂=8.0Hz). At room temperature, mixture of cis/trans amide rotamers (2/1),determined by ¹H NMR (CDCl₃) 5.02 (q, 1H, J=6.8 Hz), 5.51 (q, 1H, J=6.8Hz). MS(ESI⁺) 535.2 (MH⁺).

Synthesis of Compound 3.30

[0373]

[0374] Compound 3.30 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, m.p. 153° C. ¹H NMR (DMSO, T=140° C.)0.97 (t, 3H, J=6.8 Hz), 1.37 (t, 3H, J=6.8 Hz), 1.44 (d, 3H, J=6.8 Hz),3.31-3.59 (m, 8H), 4.10 (q, 2H, J=6.8 Hz), 5.17 (q, 1H, J=6.8 Hz),7.05-7.33 (m, 8H), 7.55 (t, 1H, J=8 Hz), 7.71 (d, 1H, J=8 Hz), 7.85 (t,1H, J=8 Hz), 8.15 (dd, 1H, J₁=1.2 Hz, J₂=8.0 Hz). At room temperature,mixture of cis/trans amide rotamers (1/1), determined by ¹H NMR (CDCl₃)4.92 (q, 1H, J=6.9 Hz), 5.35 (q, 1H, J=6.9 Hz). MS(ESI⁺) 584.3 (MH⁺).Anal. (C₃₁H₃₂F₃N₃O₅) cal. C 63.80H 5.53 N 7.20. Found C 63.92, H 5.61, N7.20.

Synthesis of Compound 3.31

[0375]

[0376] Compound 3.31 was prepared in a manner similar to that used forcompound 3.02. Colorless oil, ¹H NMR (CD₃OD) 1.18 (t, 3H, J=7.0 Hz),1.37 (t, 3H, J=7.0 Hz), 1.41 (d, 3H, J=6.6 Hz), 3.30 (s, 2H), 3.36 (m,1H), 3.52 (q, 2H, J=7.0 Hz), 3.62 (m, 2H), 3.91 (m, 1H), 4.02 (q, 2H,J=7.0 Hz), 4.75 (q, 1H, J=6.6 Hz), 6.85 (m, 1H), 6.90 (d, 2H, J=9 Hz),7.06 (m, 1H), 7.13 (m, 1H), 7.34 (d, 2H, J=4.8 Hz), 7.53 (d, 2H, J=9Hz), 7.70 (m, 1H), 8.28 (d, 2H, J=4.8 Hz) MS(ESI⁺) 501.2 (MH⁺).

Synthesis of Compound 3.32

[0377]

[0378] Compound 3.32 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, m.p. 146.3° C. ¹H NMR (DMSO, T=140°C.) 0.97 (t, 3H, J=6.8 Hz), 1.36 (t, 3H, J=6.8 Hz), 1.46 (d, 3H, J=6.4Hz), 3.32-3.59 (m, 8H), 4.09 (q, 2H, J=6.8 Hz), 5.17 (q, 1H, J=6.4 Hz),6.95-7.11 (m, 4H), 7.26 (m, 2H), 7.54 (t, 1H, J=8 Hz), 7.71 (d, 1H,J₂=7.6 Hz), 7.85 (dt, 1H, J₁=1.6 Hz, J₂=8.2 Hz), 8.15 (dd, 1H, J₁=1.2Hz, J₂=7.6 Hz). At room temperature, mixture of cis/trans amide rotamers(1/1), determined by ¹H NMR (CDCl₃) 4.92 (q, 1H, J=6.8 Hz), 5.38 (q, 1H,J=6.8 Hz). MS(ESI⁺) 554.3 (MH⁺). Anal. (C₃₀H₃₀F₃N₃O₄) cal. C 65.09H 5.46N 7.59. Found C 64.93, H 5.55, N 7.62.

Synthesis of Compound 3.33

[0379]

[0380] Compound 3.33 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, m.p. 77.7° C. ¹H NMR (DMSO, T=140°C.) 1.38 (m, 6H), 3.05 (br, 1H), 3.42 (m, 1H), 4.12 (q, 2H, J=7.2 Hz),4.71 (m, 2H), 5.26 (q, 1H, J=6.4 Hz), 7.09-7.51 (m, 9H), 7.39 (m, 1H),7.51-7.56 (m, 2H), 7.67 (d, 1H, J₂=8.4 Hz), 7.85 (t, 1H, J=8 Hz), 8.09(d, 1H, J=8.0 Hz), 8.34 (m, 1H). At room temperature, mixture ofcis/trans amide rotamers (2/1), determined by ¹H NMR (CDCl₃) 5.09 (m,1H), 5.40 (m, 1H). MS(ESI⁺) 604.2 (MH⁺). Anal. (C₃₃H₂₉F₃N₄O₄) cal. C65.77H 4.85 N 9.30. Found C 65.32, H 4.87, N 9.12.

Synthesis of Compound 3.34

[0381]

[0382] Compound 3.34 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, m.p. 75.5° C. mixture of cis/transamide rotamers (2/1), determined by ¹H NMR (CD₃OD) 5.20 (m, 1H), 5.45(m, 1H). MS(ESI⁺) 556.3 (MH⁺). Anal. (C₃₂H₂₈F₂N₄O₃) cal. C 69.30H 5.09 N10.10. Found C 68.83, H 5.15, N 9.99.

Synthesis of Compound 3.35

[0383]

[0384] Compound 3.35 was prepared in a manner similar to that used forcompound 3.02 White solid. ¹H NMR (DMSO, T=140° C.) 1.36 (t, 3H, J=6.8Hz), 1.42 (d, 3H, J=6.4 Hz), 3.05 (m, 1H), 3.53 (m, 1H), 4.11 (m, 2H),4.73 (m, 2H), 5.27 (q, 1H, J=6.4 Hz), 7.11 (m, 4H), 7.33-7.51 (m, 8H),7.68 (d, 1H, J=8 Hz), 7.83 (t, 1H, J=7.2 Hz), 8.10 (m, 1H), 8.34 (m,1H). At room temperature, mixture of cis/trans amide rotamers (7/1),determined by ¹H NMR (CDCl₃) 5.11 (q, 1H, J=6.4 Hz), 5.42 (m, 1H).MS(ESI⁺) 587.3 (MH⁺). Anal. (C₃₃H₂₉F₃N₄O₃) cal. C 67.57H 4.98 N 9.55.Found C 67.15, H 5.12, N 9.81.

Synthesis of Compound 3.36

[0385]

[0386] Compound 3.36 was prepared in a manner similar to that used forcompound 3.02. Light yellow solid, ¹H NMR (DMSO, T=140° C.) 1.39 (m,6H), 3.05 (br, 1H), 3.45 (m, 1H), 4.13 (q, 2H, J=6.8 Hz), 4.71 (m, 2H),5.26 (q, 1H, J=6.4 Hz), 7.00-7.16 (m, 8H), 7.35 (m, 2H), 7.37-7.60 (m,2H), 7.68 (d, 1H, J₂=8.4 Hz), 7.84 (t, 1H, J=8 Hz), 8.09 (d, 1H, J=8.0Hz), 8.34 (m, 1H). At room temperature mixture of cis/trans amiderotamers (1/2), determined by ¹H NMR (CDCl₃) 1.25 (d, 1H, J=6.4 Hz),1.32 (d, 1H, J=6.4 Hz). MS(ESI⁺) 603.2 (MH⁺). Anal. (C₃₃H₂₉F₃N₄O₄) cal.C 65.77H 4.85 N 9.30. Found C 65.48, H 4.98, N 9.39.

Synthesis of Compound 3.37

[0387]

[0388] Compound 3.37 was prepared following the synthesis procedure forcompound 3.02. White solid. ¹H NMR (DMSO, T=120° C.) 1.32 (t, 3H, J=7.07Hz), 1.49-1.55 (m, 6H), 1.70 (m, 1H), 2.26 (m, 1H), 2.58 (m, 1H),2.78-2.88 (m, 4H), 3.12-3.15 (m, 1H), 3.20 (m, 1H), 3.40 (m, 1H), 3.49(m, 1H), 3.50-3.85 (m, 2H), 4.07 (q, 2H, J=7.07 Hz), 5.16 (q, 1H, J=6.67Hz), 7.02 (m, 2H), 7.24 (m, 1H), 7.29-7.44 (m, 4H), 7.56 (t, 1H, J=7.33Hz), 7.72 (d, 1H, J=8 Hz), 7.86 (t, 1H, J=7.6 Hz), 8.14 (d, 1H, J=7.60Hz). MS(ESI⁺) 641.2 (MH⁺).

Synthesis of Compound 3.38

[0389]

[0390] Compound 3.38 was prepared following the synthesis of compound3.02. Pale yellow solid. ¹H NMR (DMSO, T=120° C.) 1.33 (t, 3H, J=6.67Hz), 1.51 (d, 3H, J=6.67 Hz), 2.95 (m, 1H), 3.19 (m, 1H), 3.69 (m, 1H),3.83 (m, 1H), 4.09 (q, 2H, J=6.67 Hz), 5.11-5.23 (m, 3H), 7.06 (m, 2H),7.27-7.45 (m, 7H), 7.56 (t, 1H, J=7.33 Hz), 7.70 (d, 1H, J=8 Hz), 7.85(m, 2H), 8.13 (d, 1H, J=7.60 Hz), 8.48 (s, 1H). MS(ESI⁺) 619.30 (MH⁺).

Synthesis of Compound 3.39.HCl

[0391]

[0392] Compound 3.39 was prepared following the synthesis of compound3.02. White solid. ¹H NMR (DMSO, T=120° C.) 1.36 (m, 6H), 2.88 (s, 6H),3.61 (d, 1H, J=14.67 Hz), 4.12 (q, 2H, J=6.93 Hz), 4.78 (m, 3H), 5.26(m, 1H), 6.93 (m, 1H), 7.10 (m, 2H), 7.28-7.43 (m, 5H), 7.51-7.59 (m,3H), 7.83 (t, 1H, J=7.33 Hz), 7.97 (m, 1H), 8.08 (d, 1H, J=7.73 Hz).MS(ESI⁺) 648.2 (MH⁺).

[0393] N-(4-Ethoxy-phenyl)-benzene-1,2-diamine (XIX).

[0394] In the presence of K₂CO₃ (13.0 g, 94.2 mmol), the mixture of1-fluoro-2-nitrobenzene (8.46 g, 60 mmol) and phenylamine (8.22 g, 60mmol) in DMF (40 ml) was heated to 125° C. for 16 h. and then pouredinto water, the aqueous layer was extracted with EtOAc three times, thecombined organic layer was then washed by water, brine and dried overNa₂SO4. The solvent was evaporated and the crude product wasrecrystallized from EtOH to afford a brown solid(4-ethoxy-phenyl)-(2-nitro-pheny)l-amine (10 g).

[0395] In the presence of 10% Pd-C (2.1 g, 2 mmol), under hydrogenatmosphere, a solution of (4-ethoxy-phenyl)-(2-nitro-pheny)l-amine (5.16g, 20 mmol) in MeOH/Et₂O (30 ml/30 ml) was stirred overnight. The solidwas filtered, the filtrate was evaporated to give a orange solidN-(4-ethoxy-phenyl)-benzene-1,2-diamine (3.6 g) (XIX). ¹H NMR (CDCl₃)1.39 (t, 3H, J=6.93 Hz), 3.98 (q, 2H, J=6.93 Hz), 6.78 (m, 6H), 6.94 (m,1H), 7.03 (m, 1H). MS(ESI⁺) 229.2 (MH⁺).

[0396] {1-[2-(4-Ethoxy-phenylamino)-phenylcarbamoyl]-ethyl}-carbamicAcid Tert-Butyl Ester (XX).

[0397] To a solution containing (R)—Boc-Ala-OH (4.92 g, 26 mmol) andabove diamine (5.4 g, 23.68 mmol) in 50 ml of DMF, was added EDCI (9.08g, 47.3 mmol), HOBt (3.62 g, 23.68 mmol) and NMM (3.59 g, 35.52 mmol).The mixture was stirred at room temperature overnight. The reaction wasdiluted with dichloromethane and washed with water (three times), brineand dried over Na₂SO₄. Removal of solvent afforded a oil which wassubjected to flash column. A yellow solid (7.55 g) was obtained. ¹H NMR(CDCl₃) 1.37 (m, 15H), 3.98 (q, 2H, J=5.2 Hz), 4.21 (m, 1H), 4.92 (m,1H), 5.65 (br, 1H), 6.81 (m, 4H), 6.97 (m, 1H), 7.08 (m, 2H), 7.68 (d,1H, J=8 Hz), 8.16 (s, 1H). MS(ESI⁺) 400.2 (MH⁺).

[0398] {1-[1-(4-Ethoxy-phenyl)-1H-benzoimidazol-2-yl]-ethyl}-carbamicAcid Tert-Butyl Ester (XXI).

[0399] A solution of above solid (6 g, 15.03 mmol) in HOAc (60 ml) washeated to 80° C. for 4 h. The solvent was evaporated, the residue wasdissolved in EtOAc and washed by sat. NaHCO₃, water, brine and driedover Na₂SO4. The solvent was removed and the crude residue was subjectedby flash column to afford a white solid (4.1 g). ¹H NMR (CDCl₃) 1.36 (s,9H), 1.43 (m, 6H), 4.10 (q, 2H, J=6.93 Hz), 4.84 (m, 1H), 7.03 (m, 1H),7.06 (m, 2H), 7.21 (m, 2H), 7.38 (m, 2H), 7.66 (d, 1H, J=7.73 Hz).MS(ESI⁺) 382.3 (MH⁺).

Synthesis of Compound 3.40.HCl

[0400]

[0401] Starting from{1-[1-(4-ethoxy-phenyl)-1H-benzoimidazol-2-yl]-ethyl}-carbamic acidtert-butyl ester, compound 3.40 was prepared following the synthesis ofcompound 3.02. Yellow solid. ¹H NMR (DMSO, T=120° C.) 1.35 (t, 3H,J=6.93 Hz), 1.66 (m, 3H), 3.29 (br, 1H), 3.93 (d, 1H, J=16 Hz), 4.11 (q,2H, J=6.93 Hz), 4.65 (m, 1H), 4.75 (m, 1H), 5.70 (m, 1H), 7.03 (d, 1H,J=7.73 Hz), 7.14 (d, 2H, J=8.27 Hz), 7.26-7.44 (m, 5H), 7.70-7.84 (m,5H), 8.45 (s, 2H). MS(ESI⁺) 627.2 (MH⁺).

Synthesis of Compound 3.41

[0402]

[0403] Compound 3.41 was prepared following the synthesis of compound3.40. White solid. ¹H NMR (DMSO, T=120° C.) 1.41 (t, 3H, J=6.93 Hz),1.59 (m, 3H), 3.30 (br, 1H), 3.69 (d, 1H, J=16 Hz), 4.15 (q, 2H, J=6.93Hz), 4.49-4.63 (m, 2H), 5.74 (m, 1H), 7.02-7.15 (m, 6H), 7.30-7.41 (m,3H), 7.58 (m, 2H), 8.18-8.32 (m, 3H). MS(ESI⁺) 602.3 (MH⁺).

Synthesis of Compound 3.42.HCl

[0404]

[0405] Compound 3.42 was prepared following the synthesis of compound3.02. White solid. ¹H NMR (DMSO, T=120° C.) 1.35 (t, 3H, J=6.93 Hz),1.52 (m, 3H), 1.9 (m, 6H), 2.85-3.05 (m, 3H), 3.36-3.57 (m, 4H), 3.95(m, 3H), 4.08 (q, 2H, J=6.93 Hz), 5.17 (m, 1H), 7.02-7.10 (m, 2H),7.24-7.46 (m, 5H), 7.58 (t, 1H, J=7.6 Hz), 7.75 (d, 1H, J=7.73 Hz). 7.88(t, 1H, J=7.73 Hz), 8.15 (d, 1H, J=8 Hz). MS(ESI⁺) 625.3 (MH⁺).

[0406]4-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethylamino}-piperidine-1-carboxylicAcid Tert-Butyl Ester (I).

[0407] 4-Oxo-Piperidine-1-carboxylic acid tert-butyl ester (0.468 g,2.35 mmol) was added to a solution of amine (0.6 g, 1.96 mmol) indichloroethane (10 ml) at −10C, followed by Na(OAC)₃BH (0.602 g, 2.84mmol). The mixture was kept at that temperature for 1.5 h, then warmedslowly to room temperature and stirred overnight. The solution wasdiluted with DCM, washed by sat.NaHCO₃, water, brine and dried overNa₂SO₄ The solvent was evaporated and a white solid (1.1 g) wasobtained, which was used in the next step. MS(ESI⁺) 493.3 (MH⁺).

[0408]4-{{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}-[(4-fluoro-3-trifluoromethyl-phenyl)-acetyl]-amino}-piperidine-1-carboxylicAcid Ester (II).

[0409] Pyridine (0.289 g, 3.66 mmol) was added to a mixture of I (0.6 g,1.22 mmol) and phenylacetyl chloride (0.44 g, 1.83 mmol) in toluene (15ml). The solution was heated to 60° C. for 3 h, and then poured into 1NHCl. The aqueous layer was extracted with EtOAc three times, thecombined organic layer was then washed by sat. NaHCO₃, water, brine anddried over Na₂SO4. The solvent was evaporated and the crude oil wassubjected by flash column to afford a yellow solid (540 mg). MS(ESI⁺)697.3 (MH⁺).

[0410]{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}-2-(4-fluoro-3-trifluoromethyl-phenyl)-piperidin-4-yl-acetamide(3.43).

[0411] Trifluoroacetic acid (1.77 g, 15.5 mmol) was added to a solutionof II (0.54 g, 0.77 mmol) in dichloromethane. The mixture was stirred atroom temperature for 3 h. The solvent was evaporated, the residue wasdissolved in EtOAc and washed with sat. NaHCO₃, water, brine and driedover Na₂SO4. The solvent was evaporated and the crude oil was subjectedby flash column to afford a white solid (440 mg). ¹H NMR (DMSO, T=120°C.) 1.21 (m, 1H), 1.34 (m, 4H), 1.48 (d, 3H, J=6.8 Hz), 2.16 (m, 3H),2.70-2.97 (m, 4H), 3.28 (d, 1H, J=16 Hz), 3.64 (m, 1H), 4.09 (q, 2H,J=6.8 Hz), 5.04 (m, 1H), 7.07-7.20 (m, 3H), 7.30-7.44 (m, 4H), 7.58 (t,1H, J=7.33 Hz), 7.76 (d, 1H, J=8 Hz), 7.88 (d, 1H, J=7.07 Hz), 8.14 (d,1H, J=7.73 Hz), MS(ESI⁺) 597.3 (MH⁺).

Synthesis of Compound 3.44

[0412]

[0413] Formaldehyde (37% in water) (0.016 g, 0.20 mmol) was added to asolution of T0913409 (0.06 g, 0.1 mmol) in dichloroethane (5 ml),followed by Na(OAC)₃BH (0.127 g, 0.60 mmol) at room temperature. Themixture was stirred overnight. The solution was diluted with DCM, washedby sat.NaHCO₃, water, brine and dried over Na₂SO₄. The solvent wasevaporated and the residue was purified by flash column to afford awhite solid (58 mg). ¹H NMR (DMSO, T=120° C.) 1.18 (m, 1H), 1.33 (t, 3H,J=6.8 Hz), 1.48 (d, 3H, J=6.67 Hz), 1.61 (m, 1H), 1.95 (m, 1H), 2.10 (s,3H), 2.38 (m, 2H), 2.64 (m, 1H), 2.76 (m, 1H), 2.88 (s, 2H), 3.26 (d,1H, J=16 Hz), 3.58 (m, 1H), 4.09 (d, 2H, J=6.8 Hz), 5.04 (m, 1H),7.08-7.45 (m, 7H), 7.58 (m, 1H), 7.76 (d, 1H, J=8 Hz), 7.89 (m, 1H),8.14 (d, 1H, J=7.73 Hz). MS(ESI⁺) 611.3 (MH⁺).

Synthesis of Compound 3.45

[0414]

[0415] 3-(4-Ethoxyphenyl)-2-ethyl-quinoline.

[0416] 33% Potassium hydroxide (1.3 ml) was added to a mixture ofo-amino aldehyde (0.31 g, 2.6 mmol) and ketone (0.5 g, 2.6 mmol) in 95%EtOH. The solution was heated to reflux for 2 h and then poured intowater. The aqueous layer was extracted with EtOAc three times, thecombined organic layer was then washed by water, brine and dried overNa₂SO4. The solvent was evaporated and the crude oil was subjected byflash column to afford a white solid (170 mg). ¹H NMR (CDCl₃) 1.23 (t,3H, J=7.5 Hz), 1.47 (t, 3H, J=6.93 Hz), 2.98 (q, 2H, J=7.47 Hz), 4.11(q, 2H, J=6.93 Hz), 6.98 (m, 2H, J=6.8 Hz), 7.31 (m, 2H), 7.49 (m, 1H),7.68 (m, 1H), 7.77 (d, 1H, J=8 Hz), 7.92 (s, 1H), 8.08 (d, 1H, J=8 Hz).MS(ESI⁺) 278.3 (MH⁺).

[0417] Starting from 3-(4-ethoxy-phenyl)-2-ethyl-quinoline, compound3.45 was prepared following the synthesis of compound 1.01 (IV-1.01).yellow solid. ¹H NMR (DMSO, T=120° C.) 1.35 (t, 3H, J=6.80 Hz), 1.57 (m,3H), 2.94 (br, 1H), 3.63 (d, 1H, J=16 Hz), 4.11 (q, 2H, J=6.80 Hz), 4.63(m, 2H), 5.88 (m, 1H), 7.07 (m, 5H), 7.22-7.33 (m, 3H), 7.58 (m, 2H),7.76 (t, 1H, J=7.6 Hz), 7.90 (d, 1H, J=8 Hz), 7.80-8.12 (m, 3H), 8.24(m, 1H). MS(ESI⁺) 588.3 (MH⁺).

Synthesis of Compound 3.46

[0418]

[0419](R)-2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-trifluoroethyl)-3H-quinazoline-4-one (3.46).

[0420] Compound 1 was synthesized using the method described in FIG. 4,except that 4-trifluoromethylaniline was used in place of p-phenetidine.¹H NMR (DMSO-d₆, T=120° C.) 1.40 (m, 3H), 2.89 (m, 1H), 3.58 (m, 1H),4.78 (m, 2H), 5.24 (m, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.26 (m, 2H), 7.55(m, 5H), 7.71 (m, 1H), 7.80 (br s, 1H), 7.90 (m, 3H), 8.12 (d, J=7.8 Hz,1H), 8.38 (t, J=5.1 Hz, 2H) ppm. MS (ESI⁺) m/z 611.3 [M+H]⁺.

Synthesis of Compound 3.47

[0421]

[0422](R)-2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-(1-propynyl))-3H-quinazoline-4-one (3.47).

[0423] Compound 3.47 was synthesized using the method described for thesynthesis of compound 3.07, except that excess amount of propyne gas wasused in place of trimethylsilylacetylene. ¹H NMR (DMSO-d₆, T=120° C.)1.41 (m, 3H), 2.09 (s, 3H), 2.89 (m, 1H), 3.55 (m, 1H), 4.72 (m, 2H),5.23 (m, 1H), 7.18 (m, 1H), 7.28 (m, 2H), 7.55 (m, 8H), 7.71 (m, 1H),7.87 (m, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.37 (m, 2H) ppm. MS (ESI⁺) m/z581.2 [M+H]⁺.

Synthesis of Compound 3.48

[0424]

[0425](R)-2-((N-3-Picolyl)-N-(4-trifluoromethylphenylacetyl)-1-aminoethyl)-3-(4-carboethoxymethoxy)-3H-quinazoline-4-one(3.48).

[0426] Compound 3.48 was synthesized using the method described in FIG.4, except that 4-(carboethoxymethoxy)aniline was used in place ofp-phenetidine. ¹H NMR (DMSO-d₆, T=120° C.) 1.24 (t, J=7.1 Hz, 3H), 1.39(d, J=5.4 Hz, 3H), 3.51 (br s, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.72 (br s,2H), 4.78 (s, 2H), 5.22 (m, 2H), 7.16 (m, 3H), 7.29 (d, J=7.7 Hz, 2H),7.44 (m, 1H), 7.54 (m, 4H), 7.68 (m, 2H), 7.86 (t, J=7.0 Hz, 1H), 8.10(d, J=7.0 Hz, 1H), 8.36 (br s, 2H) ppm. MS (ESI⁺) m/z 645.2 [M+H]⁺.

Synthesis of Compound 3.49

[0427]

[0428] 4-(2,2,2-trifluoroethoxy)aniline. To a mixture of 4-nitrophenol(1.39 g, 10 mmol, 1.0 equiv), and K₂CO₃ (1.8 g, 13 mmol, 1.3 equiv) in10 mL of dry DMF was added 1-iodo-2,2,2-trifluoroethane (2.31 g, 11mmol, 1.1 equiv). The mixture was heated in an oil bath at 100° C. for24 h. Half of the initial amount of K₂CO₃ and1-iodo-2,2,2-trifluoroethane were added. The mixture was stirred foranother 24 h at 100° C. This was repeated once more on the third day. Atthe end of this 72 h reaction, the mixture was cooled to roomtemperature and poured into 40 mL of water. The mixture was extractedtwice with 20 mL of diethyl ether. The combined ether extract was washedonce with 40 mL of brine, dried over anhydrous Na2SO4, filtered toremove drying agent, and evaporated in vacuo to yield 1.6 g of a crudeproduct as light yellow solid. ¹H NMR (DMSO-d₆) 4.98 (q, J=8.8 Hz, 2H),7.30 (d, J=9.2 Hz, 2H), 8.26 ((d, J=9.2 Hz, 2H) ppm.

[0429] To a solution of the crude 4-(2,2,2-trifluoroethoxy)nitrobenzene(1.6 g, 7.2 mmol, 1.0 equiv) in 40 mL of dichloromethane was added 0.4 gof a 5% palladium on activated carbon (0.19 mmol, 0.026 equiv). Hydrogengas was introduced using a balloon while the mixture was stirredvigorously for 48 h at room temperature. After all starting material hadbeen consumed, the mixture was filtered through a pad of Celite toremove the palladium catalyst. The filtrate was evaporated in vacuo togive a crude product as a brown liquid. This crude product was purifiedby distillation at reduced pressure to give 1.3 g of pure4-(2,2,2-trifluoroethoxy)aniline as a colorless liquid, which solidifiedupon cooling to 0° C. b.p. 81-83° C. at 0.5 torr;. ¹H NMR (DMSO-d₆)δ4.53 (q, J=9.1 Hz, 2H), 4.76 (br s, 2H), 6.52 (d, J=7.6 Hz, 2H), 6.76(d, J=7.6 Hz, 2H) ppm.

[0430](R)-2-((N-3-Picolyl)-N-(3,4-dichlorophenylacetyl)-1-aminoethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-3H-quinazoline-4-onetrifluoroacetate (3.49.CF₃COOH).

[0431] The trifluoroacetic acid salt of compound 3.49 was synthesizedusing the method described in FIG. 4, except that4-(2,2,2-trifluoroethoxy)aniline was used in place of p-phenetidine, andthat 3,4-dichlorophenylacetic acid was used in place of4-trifluoromethylphenylacetic acid. ¹H NMR (DMSO-d₆, T=120° C.) δ1.42(br s, 3H), 3.50 (m, 1H), 4.75 (m, 5H), 5.22 (m, 1H), 7.03 (d, J=7.9 Hz,1H), 7.27 (m, 5H), 7.43 (d, J=8.2 Hz, 1H), 7.50 (m, 1H), 7.56 (t, J=7.4Hz, 1H), 7.67 (t, J=8.4 Hz, 2H), 7.87 (t, 1H), 8.11 (d, J=7.6 Hz, 1H),8.42 (br s, 2H) ppm. MS (ESI⁺) m/z 641.2 [M+H]⁺.

Synthesis of Compound 3.50

[0432]

[0433](R)-2-((N-3-Picolyl)-N-(4-trifluoromethoxyphenylacetyl)-1-aminoethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-3H-8-azaquinazoline-4-one(5).

[0434] Compound 3.50 was synthesized using the method described in FIG.13, except that 4-(2,2,2-trifluoroethoxy)aniline was used in place ofp-phenetidine. ¹H NMR (DMSO-d₆, T=120° C.) δ1.42 (m, 3H), 3.51 (m, 1H),4.17 (m, 1H), 4.77 (q, J=8.7 Hz, 2H), 4.89 (m, 2H), 5.25 (m, 1H), 7.18(m, 4H), 7.28 (m, 3H), 7.47 (m, 1H), 7.59 (m, 2H), 7.90 (m, 1H), 8.50(m, 3H), 9.01 (m, 1H) ppm. MS (ESI⁺) m/z 658.2 [M+H]⁺.

Synthesis of Compound 3.51

[0435]

[0436](R)-2-((N-3-Picolyl)-N-(4-trifluoromethoxyphenylacetyl)-1-aminoethyl)-3-(4-(2,2,2-trifuoroethoxy)phenyl)-3H-5,6,7,8-tetrahydro-8-azaquinazoline-4-one(3.51).

[0437] To a solution of compound 3.50 (10 mg, 15 μmol, 1.0 equiv) in 1.0mL of MeOH, was added 10% Pd on activated carbon (2 mg, 1.9 μmol, 0.13equiv). Hydrogen was introduced using a balloon. The mixture was stirredvigorously for 16 h at room temperature. The mixture was diluted with 5mL of dichloromethane and filtered to removed catalyst. The filtratedwas evaporated in vacuo to give crude 6, which was purified by silicagel chromatography to give 7.3 mg 3.51 as a white solid. ¹H NMR(DMSO-d₆, T=12° C.) δ1.26 (d, J=6.5 Hz, 3H), 1.79 (m, 2H), 2.34 (t,J=6.1 Hz, 2H), 2.88 (m, 1H), 3.29 (m, 3H), 4.62 (m, 2H), 4.70 (q, J=8.8Hz, 2H), 5.07 (m, 1H), 6.43 (s, 1H), 7.00 (m, 1H), 7.16 (m, 6H), 7.29(m, 2H), 7.51 (d, 1H), 8.41 (m, 2H) ppm. MS (ESI⁺) m/z 662.2 [M+H]⁺.

Synthesis of Compound 3.52

[0438]

[0439] Compound 3.52, white solid.

[0440]¹H NMR (DMSO, T=120° C.) 8.37-8.41 (m, 2H), 8.12 (d, 1H, J=7.2Hz), 7.99 (m, 2H), 7.89 (m, 1H), 7.79 (m, 1H), 7.69 (d, 1H, J=7.0 Hz),7.53-7.61 (m, 4H), 7.09-7.23 (m, 3H), 5.23 (m, 1H), 4.68-4.81 (m, 2H),3.65-3.70 (m, 1H), 2.96-3.22 (m, 1H), 1.40 (m, 3H). MS (ESI⁺) 586.2(MH⁺).

Synthesis of Compound 3.53

[0441]

[0442] Compound 3.53, white solid.

[0443]¹H NMR (DMSO, T=120° C.) 8.35 (m, 2H), 8.10 (d, 1H, J=6.9 Hz),7.86 (t, 1H, J=7.0 Hz), 7.70 (m, 1H), 7.41-7.31 (m, 3H), 7.29 (m, 2H),7.16 (m, 8H), 6.94-7.00 (m, 3H), 5.26 (m, 1H), 4.71 (m, 2H), 4.36-4.41(m, 4H), 3.44 (m, 1H), 3.05 (m, 1H), 1.39 (m, 3H). MS (ESI⁺) 695.2(MH⁺).

Synthesis of Compound 3.54

[0444]

[0445] Compound 3.54, white solid.

[0446]¹H NMR (DMSO, T=120° C.) 8.10 (d, 1H, J=7.5 Hz), 7.86 (t, 1H,J=7.1 Hz), 7.40-7.71 (m, 9H), 7.10 (m, 4H), 5.25 (m, 1H), 4.77 (m, 2H),4.12 (q, 2H, J=7.0 Hz), 3.61 (m, 1H), 3.05 (m, 1H), 1.43 (m, 3H), 1.36(t, 3H, J=7.0 Hz). MS (ESI⁺) 629.2 (MH⁺).

Synthesis of Compound 3.55

[0447]

[0448] Compound 3.55, white solid.

[0449]¹H NMR (DMSO, T=120° C.) 8.10 (d, 1H, J=8.0 Hz), 7.86 (t, 1H,J=7.2 Hz), 7.71 (m, 1H), 7.54-7.60 (m, 2H), 7.37 (m, 1H), 7.03-7.11 (m,5H), 6.76 (m, 1H), 6.70 (m, 2H), 5.28 (m, 1H), 4.61-4.63 (m, 2H), 4.10(q, 2H, J=7.0 Hz), 3.70 (s, 3H), 3.65 (m, 1H), 3.59 (s, 3H), 2.95 (m,1H), 1.43 (m, 3H), 1.36 (q, 3H, J=7.0). MS (ESI⁺) 664.2 (MH⁺).

Synthesis of Compound 3.56

[0450]

[0451] Compound 3.56, white solid.

[0452]¹H NMR (DMSO, T=120° C.) 9.06 (s, 1H), 8.70 (d, 1H, J=5.1 Hz),8.35-8.37 (m, 2H), 7.90 (d, 1H, J=5.1 Hz), 7.55 (m, 1H), 7.41 (m, 3H),7.28-7.33 (m, 1H), 7.07-7.19 (m, 4H), 5.28 (m, 1H), 4.74 (m, 2H), 4.10(q, 2H, J=7.0 Hz), 3.60 (m, 1H), 2.86 (m, 1H), 1.45 (m, 3H), 1.35 (t,3H, J=7.0 Hz). MS (ESI⁺) 606.2 (MH⁺).

Synthesis of Compound 3.57

[0453]

[0454] Compound 3.57, white solid.

[0455]¹H NMR (DMSO, T=120° C.) 8.36 (m, 2H), 8.10 (s, 1H, J=8.1 Hz),7.87 (t, 1H, J=7.0 Hz), 7.71 (m, 1H), 7.47-7.61 (m, 6H), 7.07-7.19 (m,4H), 5.23 (m, 1H), 4.71 (m, 2H), 4.50 (s, 2H), 3.58 (m, 1H), 3.37 (s,3H), 2.90 (m, 1H), 1.43 (m, 3H). MS (ESI⁺) 605.3 (MH⁺).

Synthesis of Compound 3.58

[0456]

Compound 3.58, white solid.

[0457]¹H NMR (DMSO, T=120° C.) 8.20 (d, 1H, J=1.0 Hz), 8.17 (s, 1H),8.09 (m, 1H), 7.87 (m, 1H), 7.72 (m, 1H), 7.56 t, 1H, J=7.2 Hz),7.38-7.40 (m, 3H), 7.29-7.34 (m, 1H), 7.17 (m, 1H), 7.03-7.11 (m, 3H),5.27 (m, 1H), 4.68-4.71 (m, 2H), 4.09 (q, 2H, J=7.0 Hz), 3.52-3.58 (m,1H), 2.90 (m, 1H), 2.07 (s, 3H), 1.44-1.47 (m, 3H), 1.34 (t, 3H, J=7.0Hz). MS (ESI⁺) 619.2 (MH⁺).

Synthesis of Compound 3.59

[0458]

[0459] Compound 3.59, white solid.

[0460]¹H NMR (DMSO, T=120° C.) 8.07 (d, 1H, J=8.0 Hz), 7.85 (t, 1H,J=6.9 Hz), 7.70 (m, 1H), 7.54 (m, 1H), 7.27-7.38 (m, 4H), 7.04-7.09 (m,7H), 5.28 (m, 1H), 4.68 (m, 2H), 4.09 q, 2H, J=6.9 Hz), 3.49-3.58 (m,3H), 2.90 (m, 1H), 2.46-2.51 (m, 4H), 1.43 (m, 3H), 1.35 (t, 3H, J=6.9Hz), 0.96 (t, 6H, J=7.0 Hz). MS (ESI⁺) 688.5 (MH⁺).

Synthesis of Compound 3.60

[0461]

[0462] Compound 3.60 was prepared as outlined in Scheme II, below. Whitesolid. ¹H NMR (DMSO, T=120° C.) 9.00 (m, 1H), 8.51 (m, 1H), 7.58 (m,1H), 7.41 (m, 1H), 7.18-7.26 (m, 5H), 7.04-7.10 (m, 2H), 5.16 (m, 1H),4.11 (q, 2H, J=7.0 Hz), 3.40-3.50 (m, 7H), 2.90 (m, 1H), 2.30-2.40 (m,6H), 1.46 (m, 3H), 1.36 (t, 3H, J=7.0 Hz). MS (ESI⁺) 626.4 (MH⁺).

Synthesis of Compound 3.61

[0463]

[0464] 3.61 was synthesized following the generic synthetic scheme forthe synthesis of triazolinones (FIG. 9) to yield a colorless solid. ¹HNMR (d₆-DMSO; T=120° C.) δ8.57 (d, J=14 Hz, 2H), 7.91 (s, 1H), 7.90 (d,J=8.0 Hz, 2H), 7.58 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.41 (t, J=7.6 Hz,2H), 7.35 (d, J=8.4 Hz, 2H), 7.27 (t, J=7.6 Hz, 1H), 7.24 (d, J=7.6 Hz,2H), 7.09 (d, J=8.8 Hz, 2H), 5.50 (s, 1H), 4.73 (d, J=16.8 Hz, 1H), 4.63(d, J=16.8 Hz, 1H), 4.12 (q, J=6.8 Hz, 2H), 3.67 (d, J=16.0 Hz, 1H),3.31 (br s, 1H), 1.48 (d, J=6.8 Hz, 3H), 1.37 (t, J=6.8 Hz, 3H) ppm.MS(ESI⁺) 602.2 : (MH⁺).

Synthesis of Compound 3.62

[0465]

[0466] 3.62 was synthesized following the synthetic scheme for8-azaquinazolinones (FIG. 13) to yield a faint yellow solid. ¹H NMR(d₆-DMSO; T=120° C.) 9.02 (dd, J₁=2.0 Hz, J₂=4.4 Hz, 1H), 8.57 (br s,1H), 8.51 (br s, 1H), 8.50 (dd, J₁=1.6 Hz, J₂=8.0 Hz, 1H), 8.02 (m, 2H),7.94 (br s, 1H), 7.83 (br s, 1H), 7.67 (br s, 1H), 7.60 (dd, J₁=4.4 Hz,J₂=7.6 Hz, 1H), 7.50 (br s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.42 (d, J=6.8Hz, 1H), 7.30 (dd, J₁=J₂=8.8 Hz, 1H), 5.23 (q, J=6.4 Hz, 1H), 4.96 (d,J=18.0 Hz, 1H), 4.86 (d, J=18.0 Hz, 1H), 3.70 (d, J=16.4 Hz, 1H), 3.39(br s, 1H), 1.42 (d, J=6.4 Hz, 3H) ppm. MS(ESI⁺) 587.3 (MH⁺).

Synthesis of Compound 3.63

[0467]

[0468] Compound 3.63 was synthesized following the synthetic scheme for8-azaquinazolinones (FIG. 13) to yield a colorless solid. ¹H NMR(d₆-DMSO; T 120° C) δ9.01 (dd, J₁=1.6 Hz, J₂=4.4 Hz, 1H), 8.44 (dd,J₁=1.6 Hz, J₂=7.6 Hz, 1H), 7.55 (dd, J₁=4.8 Hz, J₂=8.0 Hz, 1H), 7.48 (d,J=8.0 Hz, 1H), 7.35-7.44 (m, 3H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.8Hz, 1H), 6.93-7.12 (m, 5H), 6.87 (dd, J₁=J₂=4.0 Hz, 1H), 5.25 (q, J=6.4Hz, 1H), 4.82 (d, J=16.4 Hz, 1H), 4.71 (d, J=16.8 Hz, 1H), 4.09 (q,J=7.2 Hz, 2H), 3.64 (d, J=15.6 Hz, 1H), 2.98 (br m, 1H), 1.49 (d, J=6.8,3H), 1.35 (t, J=6.8 Hz, 3H) ppm. MS(ESI⁺) 666.2 (MNa⁺).

Synthesis of Compound 3.64

[0469]

[0470] Compound 3.64 was synthesized following the synthetic scheme for8-azaquinazolinones (FIG. 13) to yield a yellow glassy solid. ¹H NMR(d₆-DMSO; T=120° C.) δ9.02 (dd, J₁=1.6 Hz, J₂=4.4 Hz, 1H), 8.52 (dd,J₁=2.0 Hz, J₂=8.0 Hz, 1H), 7.59 (dd, J₁=4.4 Hz, J₂=7.6 Hz, 1H),7.38-7.52 (m, 3H), 7.32 (dd, J₁=J₂=10.4 Hz, H), 7.28 (d, J=9.2 Hz, 1H),6.90-7.04 (m, 2H), 5.14 (q, J=6.4 Hz, 1H), 4.09 (q, J=6.8 Hz, 2H),3.48-3.72 (br m, 3H), 3.02-3.17 (br m, 4H), 2.77-2.98 (br m, 5H), 2.67(s, 3H), 1.51 (d, J=6.4 Hz, 3H), 1.35 (t, J=6.8 Hz, 3H) ppm. MS(ESI⁺)641.3 (MH⁺).

Synthesis of Compound 3.65

[0471]

[0472] Compound 3.65 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield acolorless solid. ¹H NMR (d₆-DMSO; T=120° C.) δ9.03 (d, J=2.8, 1H), 8.50(dd, J₁=1.6 Hz, J₂=7.6 Hz, 1H), 7.59 (dd, J₁=4.8 Hz, J₂=7.6 Hz, 1H),7.43 (d, J=8.4 Hz, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.34-7.47 (m, 1H), 7.09(d, J=8.0 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.66-6.92 (m, 3H), 5.26 (brs, 1H), 4.83 (br s, 2H), 4.08 (q, J=7.2 Hz, 2H), 3.56 (br s, 1H), 2.98(br s, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.33 (t, J=6.8 Hz, 3H) ppm. MS(ESI⁺)611.2 (MH⁺), 633.2 (MNa⁺).

Synthesis of Compound 3.66

[0473]

[0474] Compound 3.66 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield a yellowglassy solid. ¹H NMR (d₆-DMSO; T=120° C.) δ9.00 (d, J=2.4 Hz, 1H), 8.52(d, J=7.6 Hz, 1H), 7.90 (dd, J₁=4.4 Hz, J₂=7.6 Hz, 1H), 7.41-7.54 (m,3H), 7.37 (d, J=11.6 Hz, 1H), 7.32 (dd, J₁=J₂=9.2 Hz, 1H), 7.04-7.18 (m,2H), 5.10 (br s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.90-4.06 (m, 1H),3.62-3.84 (m, 1H), 3.40-3.60 (m, 1H), 2.96-3.14 (m, 1H), 2.74 (s, 3H),1.52 (d, J=6.4 Hz, 3H), 1.36 (s, 9H), 1.34 (t, J=7.2 Hz, 3H) ppm.MS(ESI⁺) 628.4 (MH⁺).

Synthesis of Compound 3.67

[0475]

[0476] Compound 3.67 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield acolorless solid. ¹H NMR (d₆-DMSO; T=120° C.) δ9.04 (dd, J₁=1.6 Hz,J₂=4.4 Hz, 1H), 8.50 (dd, J₁=2.0 Hz, J₂=7.6 Hz, 1H), 7.58 (dd, J₁=4.4Hz, J₂=8.0 Hz, 1H), 7.40 (d, J=6.8 Hz, 2H), 7.36-7.45 (m, 1H), 7.30 (dd,J₁=J₂=10.4 Hz, 1H), 7.27-7.34 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.02 (d,J=6.8 Hz, 1H), 5.23 (br s, 1H), 4.50 (d, J=15.6 Hz, 1H), 4.43 (d, J=15.6Hz, 1H), 4.09 (q, J=6.8 Hz, 1H), 3.67 (s, 3H), 2.93 (br s, 2H), 1.49 (d,J=6.4 Hz, 3H), 1.35 (t, J=6.8 Hz, 3H) ppm. MS(ESI⁺) 609.3 (MH⁺), 631.2(MNa⁺).

Synthesis of Compound 3.68

[0477]

[0478] Compound 3.68 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield a yellowglassy solid. ¹H NMR (d₆-DMSO; T=120° C.) δ9.00 (dd, J₁=2.0 Hz, J₂=4.4Hz, 1H), 8.44 (dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 7.56 (dd, J₁=4.8 Hz,J₂=8.0 Hz, 1H), 7.33-7.44 (m, 3H), 7.28 (dd, J₁=J₂=10.4 Hz, 1H), 7.06(dd, J₁=J₂=8.8 Hz, 1H), 7.05 (d, J=5.2 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H),6.52 (d, J=7.2 Hz, 2H), 5.27 (q, J=6.4 Hz, 1H), 4.65 (d, J=16.4 Hz, 1H),4.48 (d, J=16.4 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.58 (d, J=15.2 Hz,1H), 2.90 (br s, 1H), 2.82 (s, 3H), 1.45 (d, J=6.4 Hz, 3H), 1.35 (t,J=6.8 Hz, 3H) ppm. MS(ESI⁺) 670.3 (MNa⁺).

Synthesis of Compound 3.69

[0479]

[0480] Comopund 3.69 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield acolorless solid. ¹H NMR (d₆-DMSO; T=120° C.) δ9.01 (dd, J₁=2.0 Hz,J₂=4.4 Hz, 1H), 8.47 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H), 8.36 (s, 2H), 7.58(dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.08-7.22 (m,7H), 5.26 (q, J=6.8 Hz, 1H), 4.68 (br s, 2H), 4.13 (q, J=7.2 Hz, 2H),2.89 (br s, 2H), 2.11 (tt, J₁=J₂=4.4 Hz, 1H), 1.43 (d, J=6.8 Hz, 3H),1.36 (t, J=7.2 Hz, 3H), 0.84-1.00 (m, 4H) ppm. MS(ESI⁺) 645.3 (MH⁺).

Synthesis of Compound 3.70

[0481]

[0482] Compound 3.70 was synthesized following the synthetic scheme forthe generic synthesis of 8-azaquinazolinones (FIG. 13) to yield acolorless solid. ¹H NMR (d₆-DMSO; T=120° C.) δ8.09 (d, J=7.6 Hz, 1H),7.87 (dd, J₁=J₂=6.8 Hz, 1H), 7.82 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.56(dd, J₁=J₂=7.2 Hz, 1H), 7.38 (d, J=6.8 Hz, 2H), 7.30 (dd, J₁=J₂=10.4 Hz,1H), 7.22 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.6 Hz,1H), 7.03 (d, J=7.6 Hz, 1H), 6.21 (d, J=8.4 Hz, 1H), 5.23 (q, J=6.4 Hz,1H), 4.48 (br s, 2H), 4.09 (q, J=6.8 Hz, 2H), 3.54 (d, J=15.2 Hz, 1H),3.30 (br s, 1H), 2.88 (br s, 4H), 1.91-1.94 (m, 4H), 1.44 (d, J=6.4 Hz,3H), 1.34 (t, J=6.8 Hz, 3H) ppm. MS(ESI⁺) 674.3 (MH⁺).

Synthesis of Compound 3.71

[0483]

[0484] Compound 3.71 was prepared like compound 3.16a, with the pyridylside chain prepared from 2,5-dibromopyridine. White solid. ¹H NMR (DMSO,120° C.) δ8.10 (d, 1H, J=8.0 Hz), 7.86 (m, 2H), 7.73 (d, 1H, J=8.0 Hz),7.56 (dd, 1H, J₁=J₂=8.0 Hz), 7.38 (d, 3H, J=6.8 Hz), 7.31 (d, 1H, J=10.4Hz), 7.25 (d, 1H, J=8.4 Hz), 7.18 (s, 1H), 7.08 (m, 2H), 7.04 (m, 1H),6.41 (d, 1H, J=8.4 Hz), 5.23 (broad s, 1H), 4.49 (s, 2H), 4.12 (q, 1H,J=8.0 Hz) 4.09 (q, 2H, J=7.5 Hz), 3.54 (d, 1H, J=13.2 Hz), 2.95 (s, 6H),1.44 (d, 3H, J=6.4 Hz), 1.36 (t, 3H, J=8.0 Hz), 1.28 (s, 1H) ppm. MS(ESI⁺): expected 648.26 (MH⁺), found 648.3.

Synthesis of Compound 3.72

[0485]

[0486] White solid. ¹H NMR (DMSO, 120° C.) δ8.13 (d, 1H, J=8.0 Hz), 7.85(dd, 1H, J₁=J₂=7.6 Hz), 7.67 (d, 1H, J=8.0 Hz), 7.55 (dd, 1H, J₁=J₂=7.6Hz), 7.44 (m, 2H), 7.34 (d, 1H, J=12.4 Hz), 7.30 (dd, 1H, J₁=J₂=9.6 Hz),7.23 (d, 1H, J=8.0 Hz), 7.05 (m, 2H), 5.66 (broad s, 1H), 5.19 (broad s,1H), 4.08 (q, 2H, J=6.6 Hz), 3.77 (hept, 1H, J=6.6 Hz), 3.66 (m, 2H),3.31 (m, 1H), 3.01 (m, 2H), 2.94 (m, 1H), 1.49 (d, 3H, J=6.8 Hz), 1.43(tq, 2H, J=7.2 Hz), 1.35 (t, 3H, J=6.8 Hz), 1.21 (t, 3H, J=7.0 Hz), 1.17(s, 1H), 1.09 (d, 3H, J=6.8 Hz), 0.99 (d, 3H, J=5.2 Hz), 0.83 (t, 3H,J=7.4 Hz) ppm. MS (ESI⁺): expected 698.34 (MH⁺), found 698.3.

Synthesis of Compound 3.73

[0487]

[0488] Compound 3.73 was synthesized in the usual fashion, with thepyridyl fragment coming from 2,6-dibromopyridine. White solid. ¹H NMR(DMSO, 120° C.) δ8.09 (d, 1H, J=8.0 Hz), 7.83 (d, 1H, J₁=J₂=7.8 Hz),7.68 (d, 1H, J=8.0 Hz), 7.53 (dd, 1H, J₁=J₂=7.6 Hz), 7.40 (d, 2H, J=6.4Hz), 7.27 (m, 3H), 7.15 (d, 1H, J₁=J₂=7.6 Hz), 7.03 (m, 1H), 6.98 (m,1H), 6.24 (d, 2H, J=7.6 Hz), 5.91 (broad s, 1H), 5.35 (s, 1H), 4.56 (q,2H, J=16.4 Hz), 4.08 (d, 2H, J=6.8 Hz), 3.80 (s, 2H), 2.94 (s, 3H), 2.72(s, 3H), 1.35 (t, 3H, J=6.8 Hz) ppm. MS (ESI⁺): expected 634.25 (MH⁺),found 634.2.

Synthesis of Compound 3.74

[0489]

[0490] Compound 3.74 was synthesized as shown in FIG. 13, starting withthe L-alanine derivative rather than the D-Ala. White solid. ¹H NMR(DMSO, 120° C.) δ9.02 (d, 1H, J=3.6 Hz), 8.46 (dd, 1H, J₁=7.8 Hz, J₂=1.8Hz), 8.35 (s, 2H), 7.57 (dd, 1H, J₁=8.0 Hz, J₂=4.4 Hz), 7.53 (d, 1H,J=6.8 Hz), 7.43 (d, 1H, J=6.8 Hz), 7.14 (broad m, 8H), 5.29 (d, 1H,J=6.0 Hz), 4.76 (s, 2H), 4.13 (q, 2H, J=6.8 Hz), 3.46 (broad s, 1H),2.91 (s, 4H), 1.42 (d, 3H, J=6.8 Hz), 1.36 (t, 3H, J=7.0 Hz) ppm. MS(ESI⁺): expected 604.22 (MH⁺), found 604.3.

Example 4 Synthesis of Compound 4.01

[0491] The synthesis of compound 4.01 in four steps from commerciallyavailable starting materials provides another example of a3H-quinazolin-4-one synthesis in racemic form. Scheme 12 provides anoverview of the synthetic route, for which the experimental detailsfollow.

[0492] (R)-t-Butyl 2-(N-2-Ethoxyethyl)aminopropionate (XXII).

[0493] To a solution of D-alanine t-butyl ester hydrochloride (3.15 g,17.3 mmol, 1.0 equiv), and 2-bromoethyl ethyl ether (2.79 g, 18.2 mmol,1.05 equiv) in 14 mL of DMF, was added KI (1.44 g, 8.7 mmol, 0.50equiv), followed by K₂CO₃ (2.40 g, 17.3 mmol, 1.0 equiv). After stirredat 55° C. for 16 h, the reaction mixture was poured into a mixture of 70mL of water and 10 mL of 10% Na₂CO₃. The resulting mixture was extractedthree times with 50 mL of EtOAc. The organic layer was washed with 50 mLof brine, dried over Na₂SO₄ and concentrated in vacuo to give a yellowoil, which was passed through a short silica gel column, eluted withEtOAc. The eluent was concentrated in vacuo to give 3.13 g of the crudeXXII as a brown oil, which was used in subsequent step without furtherpurification. ¹H NMR (CDCl₃) δ1.20 (t, J=8.0 Hz, 3H), 1.27 (d, J=7.2 Hz,3H), 1.46 (s, 9H), 1.95 (br, 1H), 2.65 (m, 1H), 2.83 (m, 1H), 3.23 (q,J=7.2 Hz, 1H), 3.40-3.56 (m, 4H) ppm. MS (ESI⁺) m/z 218.1 [M+H]⁺.

[0494] (R)-t-Butyl2-(N-2-Ethoxyethyl)-(N-4-phenylphenylacetyl)amino-propionate (XXIII)

[0495] To a solution of crude XXII (5.0 g, 23 mmol, 1.0 equiv), and4-phenylphenylacetic acid (4.88 g, 23 mmol, 1.0 equiv) in 40 mL ofdichloromethane, was added EDC (5.51 g, 29 mmol, 1.25 equiv), HOBT (3.89g, 29 mmol, 1.25 equiv), and N-methylmorpholine (2.79 g, 28 mmol, 1.2equiv) at room temperature. The mixture was stirred at room temperaturefor 4 h. The reaction mixture was poured into a 30 mL of 5% aqueousH₃PO₄, and extracted twice with 20 mL of EtOAc. The combined EtOAcextract was washed twice with 20 mL of 10% aqueous NaHCO₃, and once with30 mL of brine. The organic layer was dried over Na₂SO₄ and evaporatedin vacuo to give a brown oil, which was purified by silica gelchromatography to give 5.05 g of compound XXIII as a light yellow oil.¹H NMR (CDCl₃) δ1.20 (t, J=8.0 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H), 1.46 (s,9H), 1.95 (br, 1H), 2.65 (m, 1H), 2.83 (m, 1H), 3.23 (q, J=7.2 Hz, 1H),3.40-3.56 (m, 4H) ppm. MS (ESI⁺) m/z 218.1 [M+H]⁺.

[0496] (R)-2-(N-2-Ethoxyethyl)-(N-4-phenylphenylacetyl)aminopropionicacid (XXIV)

[0497] To a solution of compound XXIII (5.05 g, 12.3 mmol, 1.0 equiv) in25 mL of dichloromethane, was added triethylsilane (3.57 g, 30.7 mmol,2.5 equiv), and trifluoroacetic acid (18 g, 160 mmol, 13 equiv) at roomtemperature. The mixture was stirred at room temperature for 8 h. Thereaction mixture was evaporated in vacuo to give a brown residue, whichwas dissolved in 60 mL of EtOAc and washed once with 50 mL of 0.5 Maqueous KH₂PO₄, followed by 40 mL of brine. The organic layer was driedover Na₂SO₄ and evaporated in vacuo to give a brown oil, which waspurified by silica gel chromatography to give 3.69 g of compound XXIV asa colorless oil, which solidified into a cream colored solid uponstanding at room temperature. At room temperature the product exists asmixture of cis/trans amide rotamers, ca. 4.4:1 molar ratio in DMSO. Forthe major rotamer, ¹H NMR (DMSO-d₆) δ1.12 (t, J=7.0 Hz, 3H), 1.34 (d,J=6.8 Hz, 3H3.40-3.60 (m, 6H), 3.78 (s, 2H), 4.16 (q, J=6.8 Hz, 1H),7.29 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.46 (t, J=7.4 Hz, 2H),7.59 (d, J=8.0 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H) ppm. For the minorrotamer ¹H NMR (DMSO-d₆) δ4.77 (q, J=6.8 Hz, 1H) ppm. MS (ESI⁻) m/z354.2 [M−H]⁻.

[0498]2-((N-2-Ethoxyethyl)-N-(4-phenylphenylacetyl)-1-aminoethyl)-3-(6-benzothiazolyl)-3H-quinazoline-4-one(4.01).

[0499] To a solution of anthranilic acid (69 mg, 0.50 mmol, 1.0 equiv)and compound XXIV (178 mg, 0.50 mmol, 1.0 equiv) in 1.0 mL of anhydrouspyridine was added 127 μL of triphenylphosphite (155 mg, 0.50 mmol, 1.0equiv) at room temperature. The resulting yellow solution was stirred atreflux for 2 h. 6-Aminobenzothiazole (75 mg, 0.50 mmol, 1.0 equiv) wasadded via syringe. The reaction mixture was stirred for another 3 h at100° C., cooled to room temperature, and evaporated in vacuo to give abrown residue. This residue was dissolved in 20 mL of ether. The mixturewas washed successively twice with 5 mL of 5% aqueous phosphoric acid,twice with 5 mL of 1 M NaOH, once with 5 mL of pH 7 phosphate buffer(0.5 M KH₂PO₄ and 0.5 M K₂HPO₄), and once with 10 mL of brine. Theorganic layer was dried over Na₂SO₄ and evaporated in vacuo to give abrown residue, which was purified by preparative TLC to give 19 mg ofcompound 4.01 as a light yellow solid. At room temperature, thiscompound exists as a mixture of cis/trans amide rotamers, anddiastereomers, ca. 0.33:0.30:1 molar ratio in DMSO. ¹H NMR (DMSO-d₆,T=25° C.) δ4.92 (q, J=6.8 Hz, 1H), 5.05 (q, J=6.8 Hz, 1H), & 5.27 (q,J=6.8 Hz, 1H) ppm. MS (ESI⁺) m/z 589.3 [M+H]⁺.

Synthesis of Compound 4.03

[0500]

[0501] Compound 4.03 was prepared following the synthesis of compound4.01. Yellow solid, mixture of cis/trans amide rotamers (1.5/1),determined by ¹H NMR (CDCl₃) 1.20 (t, 3H, J=7.0 Hz), 1.26 (t, 3H, J=7.0Hz). MS(ESI⁺) 577.3 (MH⁺).

Example 5 Synthesis of Compound 5.01

[0502] Synthesis of the biphenyl compound 5.01 was achieved via afour-step reaction sequence, commencing with a Suzuki coupling of1-ethyl-2-iodo-benzene and 4-ethoxyphenylboronic acid to form thebiphenyl unit. The remaining transformations install the amino alkyl andacetyl groups.

[0503] 4′-Ethoxy-2-ethyl-biphenyl.

[0504] A degassed (3× freeze-thaw cycles) mixture of 1.00 mL1-ethyl-2-iodo-benzene (6.97 mmol, 1.00 equiv), 3.47 g4-ethoxyphenylboronic acid (20.9 mmol, 3.00 equiv), and 402 mgtetrakis(triphenylphosphine)palladium(0) (0.349 mmol, 0.0501 equiv) wasdissolved in 8.0 mL toluene and 8.0 mL aqueous 2M sodium carbonatesolution and the biphasic mixture heated to 100° C. (externaltemperature, oil bath). After 16 h the reaction was cooled to roomtemperature and the organic phase separated. The aqueous layer wasextracted with 50% ethyl acetate in hexane (2×25 mL) and the combinedorganic separations dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield a yellow oil. The crude material waspurified by column chromatography on silica gel (3.5 cm o.d.×20 cm h)eluting with 5% ethyl acetate in hexane. Fractions containing product atR_(f)=0.68, 10% ethyl acetate in hexane, were combined and concentratedin vacuo to afford 1.54 g product, including impurity, as a colorlessoil; ca. 1.23 g pure product. An impurity of ca. 20%, identified as thehomocoupling product 4,4′-diethoxybiphenyl and quantified by relativeratio of integrated ¹H NMR resonance signals, was carried forward withthe product to the next step. ¹H NMR (CDCl₃) δ1.15 (t, 3H, J=7.6 Hz),1.49 (t, 3H, J=7.2 Hz), 2.65 (q, 2H, J=7.6 Hz), 4.12 (q, 2H, J=7.2 Hz),6.98 (d, 2H, J=8.4 Hz), 7.22-7.28 (m, 2H), 7.27 (d, 2H, J=8.4 Hz),7.31-7.34 (m, 2H) ppm.

[0505] 2-(1-Bromo-ethyl)-4′-ethoxy-biphenyl from4′-ethoxy-2-ethyl-biphenyl.

[0506] A mixture of 673 mg 4′-ethoxy-2-ethyl-biphenyl (2.98 mmol, 1.00equiv), 556 mg N-bromosuccinimide (3.13 mmol, 1.05 equiv), and 49 mg2,2′-azobisisobutyronitrile (0.30 mmol, 0.10 equiv) dissolved in 15 mLcarbon tetrachloride was heated to reflux in the presence of a highintensity incandescent light for 1.5 h. The reaction was cooled to 0° C.and the resulting precipitate removed by filtration. The concentratedfiltrate was subjected to iterative triturations with cold hexane (3×50mL) to afford 890 mg product as a colorless oil. The 4,4′-20diethoxybiphenyl impurity, ca. 20% quantitated by relative ratio ofintegrated ¹H NMR resonance signals, was carried forward to the nextstep with the product. ¹H NMR (CDCl₃) δ1.48 (t, 3H, J=6.8 Hz), 1.99 (d,3H, J=7.2 Hz), 4.12 (q, 2H, J=6.8 Hz), 5.33 (q, 1H, J=6.8 Hz), 7.00 (d,2H, J=8.8 Hz), 7.21 (d, 1H, J=7.6 Hz), 7.30-7.34 (m, 3H), 7.42 (dd, 1H,J₁=J₂=7.6 Hz), 7.77 (d, 1H, J=8.0 Hz)

[0507] ppm

[0508] [1-(4′-Ethoxy-biphenyl-2-yl)-ethyl]-(2-ethoxy-ethyl)-amine from2-(1-bromo-ethyl)-4′-ethoxy-biphenyl.

[0509] A mixture of 135 mg 2-(1-bromo-ethyl)-4′-ethoxy-biphenyl (0.442mmol, 1.00 equiv) and 115 μL 2-ethoxy-1-aminoethane (1.10 mmol, 2.50equiv) dissolved in 3.0 mL ethanol was heated to reflux for 20 h andthen concentrated in vacuo to remove the solvent. The concentratedreaction product was adsorbed directly onto a column of silica gel (3.5cm o.d.×12 cm h) and eluted with 3% methanol in chloroform. Fractionscontaining product at R_(f)=0.30, 10% methanol in chloroform, werecombined and concentrated in vacuo to afford 13.5 mg purified product asa yellow oil. ¹H NMR (CDCl₃) δ1.17 (t, 3H, J=7.2 Hz), 1.34 (d, 3H, J=6.8Hz), 1.47 (t, 3H, J=7.2 Hz), 2.55 (t, 2H, J=5.6 Hz), 3.37-3.50 (m, 2H),4.01 (q, 1H, J=6.4 Hz), 4.10 (q, 2H, J=6.8 Hz), 6.94 (d, 2H, J=8.8 Hz),7.15-7.22 (m, 3H), 7.27 (dd, 1H, J₁=J₂=7.6 Hz), 7.39 (dd, 1H, J₁=J₂=7.6Hz), 7.63 (d, 1H, J=7.6 Hz) ppm. MS (ESI, positive mode) 314.1

[0510] A mixture of 13.5 mg[1-(4′-ethoxy-biphenyl-2-yl)-ethyl]-(2-ethoxy-ethyl)-amine (43.1 μmol,1.00 equiv), 10.5 mg 4′-(trifluoromethyl)phenylacetic acid (51.7 μmol,1.20 equiv), 9.9 mg EDC (51.7 μmol, 1.20 equiv), and 1.0 mg HOBT (7.4μmol, 0.18 equiv) dissolved in 2.0 mL dichloromethane was stirred atroom temperature for 2 h. To the reaction solution was added 5 mLaqueous saturated sodium bicarbonate solution. The aqueous layer wasdiluted with water to 15 mL and extracted with dichloromethane (2×20mL). The combined organic separations were dried over magnesium sulfate,filtered, and concentrated in vacuo to yield a yellow oil. The crudeproduct was adsorbed onto a column of silica gel (3.5 cm o.d.×10 cm h)and eluted with 17% to 25% ethyl acetate gradient in hexane. Fractionscontaining product were combined and concentrated in vacuo to afford12.8 mg purified product as a colorless oil. ¹H NMR (d₆-DMSO; T=140° C.)δ1.04 (t, 3H, J=6.8 Hz), 1.34 (t, 3H, J=6.8 Hz), 1.44 (d, 3H, J=7.2 Hz),3.00-3.06 (m, 1H), 3.17-3.36 (m, 6H), 3.49 (d, 1H, J=16.0 Hz), 4.07 (q,2H, J=6.8 Hz), 5.43 (q, 1H, J=7.2 Hz), 6.92-6.96 (m, 2H), 7.13-7.18 (m,3H), 7.22-7.26 (m, 2H), 7.34 (ddd, 1H, J₁=1.2 Hz, J₂=7.6 Hz, J₃=8.4 Hz),7.39 (ddd, 1H, J₁=2.0 Hz, J₂=7.6 Hz, J₃=9.2 Hz), 7.53-7.59 (m, 3H) ppm.At room temperature, compound exists as a mixture of cis/trans amiderotamers in ca. 2:1 ratio as determined by integration of characteristic¹H NMR signals (CDCl₃; T=25° C.) δ_(major) 5.19 (q, 2.1H, J=7.2 Hz) andδ_(minor) 5.89 (q, 1.0H, J=7.6 Hz) ppm. MS (ESI, positive mode) 500.1[MH]⁺

Example 6 Synthesis of Compound 6.01

[0511]

[0512] A mixture of compound 3.22 (13 mg) and ammonium acetate (500 mg)in acetic acid (2 mL) was stirred at 80° C. for 14 h and at 100° C. for10 h. The acetic aid was evaporated, and the residue was taken by EtOAc.It was washed with sodium bicarbonate and brine, dried, andconcentrated. The residue was purified by column (70% EtOAc in Hexane)to give 10 mg of compound 6.01. ¹H NMR (CDCl₃) δ8.26 (d, J=8.0 Hz, 1H),7.84 (m, 2H), 7.56 (m, 1H), 7.46 (m, 2H), 7.32 (m, 2H), 7.18 (m, 1H),7.05 (m, 2H), 6.60 (s, 1H), 6.53 (m, 1H), 4.90 (q, 1H), 3.76 (d, 1H),2.62 (d, 1H), 2.16 (s, 3H), 1.27 (d, 3H). MS (ESI⁺) 507.2 [MH]⁺.

[0513] Into a mixture of bromide (0.557 mmol, 0.20 g) and K₂CO₃ (0.89mmol, 0.123 g) in 3 mL of DMF was added 2-undecyl-1-H-imidazole (0.557mmol, 0.124 g). The reaction mixture was heated to 90° C. for 10 h.After evaporating the solvent, the residue was dissolved in CH₂Cl₂, theorganic layer was washed by water, brine, dried over NaSO₄ and removedin vacuo to give a sticky oil which was purified by chromatography toafford a yellow solid (0.16 g). ¹H NMR (CDCl₃) 0.89 (t, 3H, J=7.0 Hz),1.25 (m, 16H), 1.60 (br m, 3H), 1.73 (d, 3H, J=6.7 Hz), 1.83 (m, 1H),3.84 (s, 3H), 5.09 (q, 1H, J=6.7 Hz), 6.35 (m, 1H), 6.84-6.90 (m, 3H),7.05 (m, 1H), 7.20 (m, 1H), 7.55 (m, 1H), 7.82 (m, 2H), 8.28 (dd, 1H,J₁=1.1 Hz, J₂=7.9 Hz). MS(ESI⁺) 501.2 (MH⁺). Anal. (C₃H₄₀N₄O₂) cal. C74.22H 8.05, N 11.19. Found C 74.22, H 8.14, N 11.03.

[0514] The synthesis of compound 6.03 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.27 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.74 (s, 1H), 7.57 (m,1H), 7.48 (m, 2H), 7.21 (m, 2H), 7.02 (m, 3H), 6.64 (m, 1H), 5.10 (q,J=6.8 Hz, 1H), 4.12 (q, 2H), 3.83 (d, J=16.4 Hz, 1H), 2.95 (d, J=16.2Hz, 1H), 1.49 (t, 3H), 1.32 (d, J=6.7 Hz, 3H). MS (ESI⁺) 544.2 [MH]⁺.

[0515] The synthesis of compound 6.04 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.26 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.54 (m, 1H), 7.47 (m,2H), 7.18 (m, 2H), 7.03 (m, 2H), 6.96 (m, 1H), 6.87 (s, 1H), 6.56 (m,1H), 5.01 (q, J=6.8 Hz, 1H), 4.11 (q, 2H), 3.71 (d, J=16.4 Hz, 1H), 2.83(m, 2H), 2.76 (d, J=16.2 Hz, 1H), 2.69 (m, 2H), 1.47 (t, 3H), 1.27 (d,J=6.7 Hz, 3H). MS (ESI⁺) 572.3 [MH]⁺.

[0516] The synthesis of compound 6.05 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.26 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.54 (m, 1H), 7.47 (m,2H), 7.18 (m, 2H), 7.06 (m, 2H), 6.96 (m, 1H), 6.78 (s, 1H), 6.52 (m,1H), 5.01 (q, J=6.8 Hz, 1H), 4.11 (m, 3H), 3.64 (m, 2H), 3.34 (s, 3H),2.81 (m, 2H), 2.68 (d, J=16.2 Hz, 1H), 1.47 (t, 3H), 1.24 (d, J=6.7 Hz,3H). MS (ESI⁺) 577.1 [MH]⁺.

[0517] The synthesis of compound 6.06 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.36 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.56 (m,1H), 7.47 (m, 3H), 7.16 (m, 2H), 7.04 (m, 3H), 6.92 (m, 2H), 6.50 (s,1H), 6.29 (m, 1H), 4.92 (q, J=6.8 Hz, 1H), 4.11 (q, 2H), 3.74 (d, J=16.4Hz, 1H), 3.08 (m, 2H), 2.98 (m, 2H), 2.59 (d, J=16.2 Hz, 1H), 1.47 (t,3H), 1.17 (d, J=6.7 Hz, 3H). MS (ESI⁺) 624.2 [MH]⁺.

[0518] The synthesis of compound 6.07 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.26 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.54 (m, 1H), 7.47 (m,2H), 7.18 (m, 2H), 7.05 (m, 2H), 6.96 (m, 1H), 6.72 (s, 1H), 6.48 (m,1H), 5.00 (q, J=6.8 Hz, 1H), 4.11 (q, 2H), 4.04 (q, 2H), 3.80 (d, J=16.4Hz, 1H), 2.85 (m, 2H), 2.65 (m, 3H), 1.47 (t, 3H), 1.23 (d, J=6.7 Hz,3H), 1.14 (t, 3H). MS (ESI⁺) 619.1 [MH]⁺.

[0519] The synthesis of 6.08 is shown in FIG. 16. ¹H NMR (CDCl₃) δ8.53(m, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.50 (m, 5H), 7.26 (m,5H), 7.07 (m, 3H), 7.00 (m, 1H), 6.61 (m, 1H), 5.03 (q, J=6.8 Hz, 1H),4.11 (q, 2H), 3.89 (d, J=16.4 Hz, 1H), 2.81 (d, J=16.2 Hz, 1H), 1.47 (t,3H), 1.27 (d, J=6.7 Hz, 3H). MS (ESI⁺) 622.1 [MH]⁺.

[0520] The synthesis of compound 6.09 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.27 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.53 (m, 1H), 7.48 (m,3H), 7.25 (s, 1H), 7.20 (m, 2H), 7.05 (m, 2H), 7.00 (m, 1H), 6.58 (m,1H), 6.50 (d, J=15.8 Hz, 1H), 5.04 (q, J=6.8 Hz, 1H), 4.21 (q, 2H), 4.12(q, 2H), 3.83 (d, J=16.4 Hz, 1H), 2.80 (d, J=16.2 Hz, 1H), 1.48 (t, 3H),1.28 (d, J==6.7 Hz, 3H). MS (ESI⁺) 617.2 [MH]⁺.

[0521] The synthesis of compound 6.10 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.26 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.54 (m, 1H), 7.47 (m,2H), 7.19 (m, 2H), 7.06 (m, 3H), 6.96 (m, 1H), 6.59 (m, 1H), 5.04 (q,J=6.8 Hz, 1H), 4.44 (s, 2H), 4.11 (m, 3H), 3.60 (m, 2H), 2.70 (d, J=16.2Hz, 1H), 1.47 (t, 3H), 1.24 (d, J=6.7 Hz, 3H). MS (ESI⁺) 577.5 [MH]⁺

[0522] The synthesis of compound 6.11 is shown in FIG. 16. ¹H NMR(CDCl₃) δ8.27 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.54 (m, 1H), 7.46 (m,2H), 7.19 (m, 2H), 7.04 (m, 2H), 6.97 (m, 2H), 6.54 (m, 1H), 5.03 (q,J=6.8 Hz, 1H), 4.53 (s, 2H), 4.11 (q, 2H), 3.75 (d, J=16.4 Hz, 1H), 2.73(d, J=16.2 Hz, 1H), 1.47 (t, 3H), 1.27 (d, J=6.7 Hz, 3H). MS (ESI⁺)549.5 [MH]⁺.

Example 7

[0523]

[0524] Compound 7.01.

[0525] To a solution of the amine (1 mmol, 0.37 g) anddiisopropylethylamine (1.2 mmol, 0.16 g) in acetonitrile (3 mL) andmethylene chloride (3 mL) was added octanesulfonyl chloride (1.2 mmol,0.26 g). The reaction mixture was stirred at room temperature overnight.Sodium carbonate (15%) was added and the aqueous layer was extractedwith methylene chloride. The organic layer was washed with water, brine,dried over NaSO₄ and concentrated in vacuo to give a yellow oil, whichwas purified by chromatography on silica gel (eluent: CHCl₃/MeOH=10/1.5)to afford a light yellow glassy oil (0.22 g). ¹H NMR (CDCl₃) 0.86 (t,3H, J=7.2 Hz), 1.17-1.25 (m, 10H), 1.46 (d, 3H, J=6.9 Hz), 1.70 (m, 2H),2.19 (s, 6H), 2.45 (m, 2H), 2.73-2.90 (m, 2H), 3.62-3.78 (m, 2H), 3.87(s, 3H), 4.88 (q, 1H, J=6.9 Hz), 7.04-7.14 (m, 3H), 7.31-7.34 (m, 1H),7.49 (dt, 1H, J₁=1.3 Hz, J₂=8 Hz), 7.68 (d, 1H, J=7.3 Hz), 7.77 (dd, 1H,J₁=2.1 Hz, J₂=8 Hz), 8.27 (dd, 1H, J₁=1.2 Hz, J₂=8 Hz). MS(ESI⁺) 544.2(MH⁺). Anal. (C₂₉H₄₂N₄O₄S) cal. C 64.18H 7.80, N 10.32, S 5.91. Found C64.36, H 7.81, N 10.08, S 5.78

Example 8

[0526]

[0527] Compound 8.01.

[0528] Compound 8.01 was prepared using the similar condition forsynthesis of compound 4.01. Oil. Mixture of cis/trans amide rotamers(1/6), determined by ¹H NMR (CDCl₃) 4.18 (q, 1H, J=7.0 Hz), 4.69 (q, 1H,J=7.0 Hz). MS(ESI⁺) 533.2 (MH⁺).

Example 9

[0529]

[0530] 2-Amino-N-(4-ethoxy-phenyl)benzamide (XX).

[0531] A mixture of isotoic anhydride (16.3 g, 100 mmol) andp-phenetidine (13.7 g, 100 mmol) was heated at 120° C. for 4 h. Thereaction mixture after cooling was triturated with ether. The resultingsolid was collected by suction to give compound XX, ¹H NMR (CD₃OD) 1.37(t, 3H, J=7.0 Hz), 4.01 (q, 2H, J=7.0 Hz), 6.67 (t, 1H, J=7.0 Hz), 6.78(dd, 1H, J₁=1.2 Hz, J₂=8.2 Hz), 6.89 (m, 2H), 7.20 (dt, 1H, J₁=1.4 Hz,J₂=8.2 Hz), 7.47 (m, 2H), 7.56 (dd, 1H, J₁=1.4 Hz, J₂=9.3 Hz).MS(ESI⁺)257.3 (MH⁺).

[0532] Synthesis of o-diamide XXI.

[0533] To a mixture of compound XX (7.68 g, 30 mmol) andN-(9-fluorenylmethyloxycarbonyl)-D-alanine (10.26 g, 33 mmol) in CH₂Cl₂(150 mL), was added EDAC (8.63 g, 45 mmol) and HOBt (1.38 g, 9 mmol).After stirring at room temperature overnight, the resulting solid wasfiltered and washed with ethyl ether to yield compound XXI (14.50 g). ¹HNMR (CDCl₃) 1.37 (t, 3H, J=7.0 Hz), 1.48 (d, 3H, J=7.2 Hz), 3.89 (m,2H), 4.26 (m, 2H), 4.45 (m, 2H), 5.50 (m, 1H), 6.76 (m, 2H), 7.17 (t,1H, J=7.3 Hz), 7.25-7.76 (m, 12H), 8.62 (d, 1H, J=8.8 Hz), 11.43 (s,1H).MS(ESI⁺) 550.3 (MH⁺).

[0534] 4-Oxoquinazoline XXII.

[0535] To a solution of diamide XXI (7.27 g, 13.27 mmol) in CH₂Cl₂, wasadded PPh₃ (17.40 g, 66.39 mmol), 12 (16.52 g, 65.02 mmol) andN,N-diisopropylethylamine(17.12 g, 132.7 mmol). The reaction mixture wasstirred at room temperature overnight. The resulting solid was filteredand washed with ethyl ether to yield compound XXII (4.83 g). ¹H NMR(CDCl₃) 1.43 (t, 3H, J=7.0 Hz), 1.52 (d, 3H, J=7.2 Hz), 4.03 (m, 2H),4.23 (m, 1H), 4.43 (m, 2H), 4.66 (m, 1H), 5.58 (m, 2H), 6.88 (m, 2H),7.23-7.78 (m, 13H), 8.46 (d, 1H, J=8.8 Hz).MS(ESI⁺) 532.3 (MH⁺).

[0536] Compound XXIII.

[0537] Piperidine (15 ml) was added to a solution of compound XXII (2.68g, 5.05 mmol) in DMF (100 ml). After stirring at room temperature for 1h, the mixture was poured into 150 ml of water, the aqueous layer wasextracted with CH₂Cl₂, the combined organic extracts was dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to give a white solid (0.80 g). ¹H NMR (CDCl₃) 1.30 (d,3H, J=6.6 Hz), 1.46 (t, 3H, J=6.3 Hz), 3.82 (m, 1H), 4.10 (q, 2H, J=6.6Hz), 7.03 (dd, 2H, J₁=1.9 Hz, J₂=7.0 Hz), 7.18 (m, 2H), 7.47 (m, 1H),7.75 (m, 2H), 8.26 (d, 1H, J=8 Hz). MS(ESI⁺) 310.1 (MH⁺).

[0538] Compound XXIV.

[0539] To a mixture of compound XXIII (0.06 g, 0.19 mmol) andbromoacetamide (0.032 g, 0.23 mmol) in DMF (3 mL), was added K₂CO₃(0.079 g, 0.57 mmol) and NaI (0.086 g, 0.57 mmol). After stirring atroom temperature overnight, evaporated the solvent, the residue wasdissolved in CH₂Cl₂, the organic layer was washed by water, brine, driedover NaSO₄ and removed in vacuo to give a yellow solid which waspurified by chromatography to afford a white solid. ¹H NMR (CDCl₃) 1.26(t, 3H, J=7.2 Hz), 1.38 (d, 3H, J=6.6 Hz), 3.46 9br, 1H), 3.58 (br, 1H),3.82 (m, 1H), 4.11 (m, 2H), 5.68 (br, 1H), 7.04 (m, 2H), 7.14 (m, 2H),7.50 (m, 1H), 7.75 (m, 2H), 8.30 (d, 1H, J=8 Hz). MS(ESI⁺) 367.3 (MH⁺).

[0540] Synthesis of Compound 9.01

[0541] Compound 9.01 was prepared using the similar condition forsynthesis of compound 3.02, white solid, mixture of cis/trans amiderotamers (1/5), determined by ¹H NMR (CDCl₃) 4.85 (q, 1H, J=7.3 Hz),5.35 (q, 1H, J=7.3 Hz). MS(ESI⁺) 561.2 (MH⁺).

Synthesis of Compound 9.02

[0542]

[0543] Compound 9.02 was prepared following the synthesis of compound9.01, oil, mixture of cis/trans amide rotamers (1/1), determined by ¹HNMR (CDCl₃) 4.95 (m, 1H), 5.35 (m, 1H). MS(ESI⁺) 630.2 (MH⁺).

Synthesis of Compound 9.03

[0544]

[0545] Compound 9.03 was prepared following the synthesis of compound9.01. Yellow solid, m.p. 167.9° C., mixture of cis/trans amide rotamers(1/2), determined by ¹H NMR (CDCl₃) 4.85 (q, 1H, J=7.0 Hz), 5.26 (q, 1H,J=7.0 Hz). MS(ESI⁺) 604.2 (MH⁺). Anal. (C₃₄H₂₉F₄N₃O₃) cal. C 67.65H 4.84N 6.96. Found C 67.80, H 4.98, N 6.97.

Synthesis of Compound 9.04

[0546]

[0547] Compound 9.04 was prepared following the synthesis of compound9.01. white solid, m.p. 156.2° C. ¹H NMR (DMSO, T=140° C.) 1.45 (d, 3H,J=6.8 Hz), 3.59-3.73 (m, 6H), 3.92 (m, 2H), 5.14 (q, 1H, J=6.8 Hz), 7.33(m, 5H), 7.69 (m, 4H), 7.72 (d, 1H, J=8 Hz), 7.86 (m 1H), 8.14 (dd, 1H,J₁=1.2 Hz, J₁=8.4 Hz), At room temperature, mixture of cis/trans amiderotamers (1/2), determined by ¹H NMR (CDCl₃) 4.88 (q, 1H, J=6.8 Hz),5.27 (q, 1H, J=6.8 Hz). MS(ESI⁺) 604.2 (MH⁺). Anal. (C₂₉H₂₄F₇N₃O₃) cal.C 58.49H 4.06 N 7.06. Found C 58.53, H 4.18, N 7.05.

Synthesis of Compound 9.05

[0548]

[0549] Compound 9.05 was prepared following the synthesis of compound9.01. Yellow solid, mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.88 (q, 1H, J=7.0 Hz), 5.35 (q, 1H, J=7.0Hz). MS(ESI⁺) 518.3 (MH⁺). Anal. (C₃₀H₃₂ FN₃O₄) cal. C 69.62H 6.23 N8.12. Found C 69.40, H 6.26, N 7.98.

Synthesis of Compound 9.06

[0550]

[0551] Compound 9.06 was prepared following the synthesis of compound9.01. Yellow solid, mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.90 (q, 1H, J=7.0 Hz), 5.35 (q, 1H, J=7.0Hz). MS(ESI⁺) 518.3 (MH⁺). Anal. (C₃₀H₃₂FN₃O₄) cal. C 69.62H 6.23 N8.12. Found C 69.33, H 6.20, N 8.06.

Synthesis of Compound 9.07

[0552]

[0553] Compound 9.07 was prepared following the synthesis of compound9.01. Yellow solid, mixture of cis/trans amide rotamers (1/1),determined by ¹H NMR (CDCl₃) 4.88 (q, 1H, J=7.0 Hz), 5.37 (q, 1H, J=7.0Hz). MS(ESI⁺) 536.3 (MH⁺). Anal. (C₃₀H₃₁F₂N₃O₄) cal. C 67.28H 5.83 N7.85. Found C 67.28, H 5.80, N 7.78.

Synthesis of Compound 9.08

[0554]

[0555] Compound 9.08 was prepared following the synthesis of compound9.01. Yellow solid, m.p. 157.9° C. ¹H NMR (DMSO, T=140° C.) 0.95 (t, 3H,J=6.4 Hz), 1.34 (t, 3H, J=6.8 Hz), 1.44 (d, 3H, J=6.8 Hz), 3.31-3.59 (m,8H), 4.08 (q, 2H, J=6.8 Hz), 5.17 (q, 1H, J=6.8 Hz), 7.02 (m, 2H),7.24-7.56 (m, 7H), 7.70 (d, 1H, J=8 Hz), 7.84 (dt, 1H, J₁=1.6 Hz, J₂=7.2Hz), 8.13 (d, 1H, J=8 Hz). At room temperature, mixture of cis/transamide rotamers (1/1), determined by ¹H NMR (CDCl₃) 4.92 (q, 1H, J=7.0Hz), 5.38 (q, 1H, J=7.0 Hz). MS(ESI⁺) 568.3 (MH⁺). Anal. (C₃₁H₃₂F₃N₃O₄)cal. C 65.60H 5.68 N 7.40. Found C 65.38, H 5.61, N 7.34.

Synthesis of Compound 9.09

[0556]

[0557] Compound 9.09 was prepared following the synthesis of compound9.01. Colorless oil, ¹H NMR (CDCl₃) 1.04 (t, 3H, J=6.9 Hz), 1.46 (m,6H), 3.30 (m, 2H), 3.42 (m, 2H), 3.62 (m, 2H), 4.08 (q, 2H, J=7.0 Hz),5.15 (q, 1H, J=7.0 Hz), 7.02 (m, 2H), 7.18 (m, 1H), 7.42-7.54 (m, 8H),7.75 (m, 1H), 8.28 (d, 1H, J=7.8 Hz) MS(ESI⁺) 536.3 (MH⁺).

Example 10

[0558]

[0559] A mixture of compound XV (160 mg, 0.5 mmol) and2-imidazolcarboxaldehyde (58 mg, 0.6 mmol) in methanol (10 mL) wasstirred at room temperature for 20 minutes. Then sodium cyanoborohydride(38 mg, 0.6 mmol) was added. The mixture was stirred at room temperaturefor 6 h. The reaction mixture was treated with EtOAc, and it was washedwith sodium bicarbonate and brine, dried, and concentrated. The residuewas purified by column (5% methanol and 1% conc. NH₄OH in 3:7 EtOAc/DCM)to give 120 mg of compound XXV. ¹H NMR (CDCl₃) δ8.25 (d, J=8.0 Hz, 1H),7.78 (t, J=8.0 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H),7.20-7.05 (m, 4H), 6.93 (s, 2H), 3.94 (d, J=14.8 Hz, 1H), 3.77 (d,J=14.8 Hz, 111), 3.38 (q, J=6.6 Hz, 1H), 1.25 (d, J=6.6 Hz, 3H).

[0560] EDC (123 mg, 0.64 mmol) was added to a mixture of compound XXV(115 mg, 0.32 mmol), 4-trifluoromethylphenyl acetic acid (65 mg, 0.32mmol), HOBt (43 mg, 0.32 mmol), and NMM (0.07 mL, 0.64 mmol) in DMF (3mL). The mixture was stirred at room temperature for 14 h. The reactionmixture was treated with EtOAc, and it was washed with sodiumbicarbonate and brine, dried, and concentrated. The residue was purifiedby column (5% methanol and 1% conc. NH₄OH in 3:7 EtOAc/DCM) to give 100mg of compound 10.01. MS (ESI⁺) 550.2 [MH]⁺.

Synthesis of Compound 10.02

[0561]

[0562] Potassium carbonate (97 mg, 0.7 mmol) was added to a mixture ofcompound 10.01 (38 mg, 0.07 mmol) and iodomethane (0.044 mL, 0.7 mmol)in DMF (2 mL). The mixture was stirred at room temperature for two days.DMF was evaporated under high vacuum, and the residue was taken byEtOAc. It was washed with brine, dried, and concentrated. The residuewas purified by column (2% methanol and 0.5% conc. NH₄OH in 3:7EtOAc/DCM) to give 15 mg of compound 10.02. MS (ESI⁺) 564.2 [MH]⁺.

Synthesis of 10.03

[0563]

[0564] Compound 10.03 was prepared following the synthetic procedure forcompound 10.01, described above. MS (ESI⁺) 550.2 [MH]⁺.

Synthesis of Compound 10.04

[0565]

[0566] Compound 10.04 was prepared following the synthetic procedure forcompound 10.02, described above. MS (ESI⁺) 564.2 [MH]⁺.

Synthesis of Compound 10.05

[0567]

[0568] Compound 10.05 was prepared following the synthetic procedure ofcompound 10.01, described above. ¹H NMR (d₆-DMSO, T=140° C.) δ8.11 (d,J=8.0 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.60-7.40(m, 6H), 7.38-7.15 (m, 5H), 5.33 (bs, 1H), 5.02 (dd, J=11.4 Hz, 2H),3.60 (bm, 2H), 1.45 (d, J=7.0 Hz, 3H). m.p. 173-174° C. MS (ESI⁺) 567.2[MH]⁺. Anal. Calcd. for C₂₉H₂₂F₄N₄O₂S: C, 61.48; H, 3.91; N, 9.89.Found: C, 61.36; H, 4.08; N, 9.75.

Example 11

[0569]

[0570] The synthesis of compound 11.01 is shown in FIG. 14. ¹H NMR(d₆-DMSO, T=120° C.) δ8.8-7.0 (m, 17H), 6.35 (s, 1H), 5.00 (m, 1H), 4.35(m, 1H), 4.25-4.00 (m, 4H), 3.65 (m, 1H), 1.40 (t, 3H). MS (ESI⁺) 619.1[MH]⁺.

Preparation of Compound 11.02

[0571]

[0572] The synthesis of compound 11.02 is shown in FIG. 17. ¹H NMR(d₆-DMSO, T=150° C.) δ8.38 (m, 2H), 8.09 (m, 1H), 7.84 (m, 2H), 7.68 (m,1H), 7.54 (m, 2H), 7.40-7.00 (m, 6H), 5.25 (m, 1H), 4.74 (m, 2H), 4.25(m, 1H), 4.14 (m, 3H), 3.62 (m, 1H), 3.31 (m, 1H), 2.78 (m, 2H), 1.37(m, 6H). MS (ESI⁺) 605.3 [MH]⁺.

Preparation of Compound 11.03

[0573]

[0574] The synthesis of compound 11.03 is shown in FIG. 18. ¹H NMR(d₆-DMSO, T=150° C.) δ9.02 (s, 1H), 8.85 (s, 1H), 8.40 (s, 1H), 8.38 (m,1H), 7.57 (m, 1H), 7.41 (m, 3H), 7.33-7.15 (m, 5H), 5.30 (q, 1H), 4.80(dd, 2H), 4.13 (q, 2H), 3.64 (d, 1H), 3.21 (bs, 1H), 1.46 (d, 3H), 1.37(t, 3H). MS (ESI⁺) 607.2 [MH]⁺.

Preparation of Compound 11.04

[0575]

[0576] The synthesis of compound 11.04 is shown in FIG. 18. ¹H NMR(d₆-DMSO, T=150° C.) δ8.81 (d, 1H), 8.38 (s, 1H), 8.35 (m, 1H), 8.03 (m,1H), 7.81 (m, 1H), 7.54 (m, 1H), 7.40 (m, 3H), 7.33-7.05 (m, 5H), 5.28(q, 1H), 4.75 (dd, 2H), 4.13 (q, 2H), 3.60 (d, 1H), 3.19 (bs, 1H), 1.44(d, 3H), 1.37 (t, 3H). MS (ESI⁺) 606.2 [MH]⁺.

Preparation of Compound 11.05

[0577]

[0578] The synthesis of compound 11.05 is shown in FIG. 11. ¹H NMR(d₆-DMSO, T=150° C.) δ8.47 (s, 1H), 8.37 (d, 1H), 8.13 (d, 1H),7.66-7.25 (m, 7H), 7.25-7.10 (m, 6H), 6.59 (d, 1H), 5.25 (q, 1H), 4.86(dd, 2H), 4.18 (q, 2H), 3.70 (d, 1H), 3.31 (bd, 1H), 1.41 (m, 6H). MS(ESI⁺) 605.2 [MH]⁺.

Preparation of Compound 11.06

[0579]

[0580] The synthesis of compound 11.06 is shown in FIG. 3. ¹H NMR(d₆-DMSO, T=150° C.) δ8.30 (m, 1H), 8.22 (s, 1H), 7.95 (m, 2H), 7.83 (m,1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.36 (m, 2H), 7.24 (m, 2H), 7.15-6.95(m, 6H), 5.45 (q, 1H), 4.50 (dd, 2H), 4.14 (q, 2H), 3.57 (d, 1H), 3.05(bd, 1H), 1.54 (d, 3H), 1.38 (t, 3H). MS (ESI⁺) 587.3 [MH]⁺.

Preparation of Compound 11.07

[0581]

[0582] The synthesis of compound 11.07 is shown in FIG. 1. ¹H NMR(CDCl₃) δ8.30 (m, 3H), 7.85 (m, 2H), 7.52 (m, 3H), 7.23 (m, 1H), 7.11(m, 1H), 7.03 (m, 2H), 6.82 (d, 1H), 6.75 (d, 1H), 6.54 (m, 1H), 5.07(q, 1H), 4.60 (dd, 2H), 4.05 (m, 3H), 3.82 (m, 2H), 1.85 (d, 1H), 1.45(t, 3H), 1.17 (s, 9H). MS (ESI⁺) 677.3 [MH]⁺.

Example 12

[0583] This example illustrates a CXCR3 binding assay that can be usedfor evaluating the compounds of the present invention.

[0584] Unless otherwise noted, all reagents used are available fromcommercial sources (e.g., Sigma). Test compounds are diluted in DMSO toa concentration that is 40-times the intended final assay concentration;5 μL are transferred to each well of a 96-well flat-bottomedpolypropylene plate (e.g., from Greiner, Inc.). CXCR3-expressing cellsobtained from ChemoCentryx were used in the assays to generate the dataset forth in the Table provided in FIG. 12. The cells were resuspendedin assay buffer (25 mM Hepes, 80 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, 0.2%bovine serum albumin, pH 7.1, stored at 4° C.) at 5 million cells permL; 100 μL of this cell suspension is then transferred to each well of a96-well plate containing the diluted test compounds. ¹²⁵I-labelledchemokine (purchased from commercial sources, e.g., Amersham, PE LifeSciences) is diluted in assay buffer to a concentration of approximately60 pM; 100 μL of this chemokine solution is transferred to each well ofa 96-well plate containing compounds and cell suspension. The plates aresealed with commercially available foil plate seals (e.g., from E&KScientific), and stored at 4° C. for 2 to 4 h, shaking gently. At theend of this incubation period, the contents of the assay plates aretransferred to GF/B filter plates (Packard) that have been pre-coated bydipping into a solution containing 0.3% polyethyleneimine (Sigma), usinga cell harvester (Packard), and washing twice with wash buffer (25 mMHepes, 500 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, pH 7.1, stored at roomtemperature). The filter plates are sealed on the bottom with plateseals (Packard), 50 μL of Microscint-20 scintillation fluid (Packard) isadded to each well, and the top of the plates are sealed with clearplastic (TopSeal A, Packard). The plates are counted on a scintillationcounter, such as a Packard TopCount. To measure non-specific binding, 4wells containing unlabelled “cold” chemokine were included on each96-well plate. To measure maximum binding, 4 wells containing 5 μL ofDMSO, 100 μL of cell suspension and 100 μL of ¹²⁵I-labelled chemokinesolution were included on each 96-well plate. Data were analyzed usingcommercially available software (e.g., Excel from Microsoft, Prism fromGraphPad Software Inc.).

[0585] Other assays may be used to identify compounds that modulateCXCR3 chemokine receptor activity, for example, binding assays (see,e.g., Weng et al. (1998) J. Biol. Chem. 273:18288-18291, Campbell et al.(1998) J. Cell Biol. 141:1053-1059, Endres et al. (1999) J. Exp. Med.189:1993-1998 and Ng et al. (1999) J. Med. Chem. 42:4680-4694), calciumflux assays (see, e.g., Wang et al. (2000) Mol. Pharm. 57:1190-1198 andRabin et al. (1999) J. Immunol. 162:3840-3850) and chemotaxis assays(see, e.g., Albanesi et al. (2000) J. Immunol. 165:1395-1402 andLoetscher et al. (1998) Eur. J. Immunol. 28:3696-3705).

[0586] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A compound having the formula (I):

wherein X is a member selected from the group consisting of a bond,—C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═, —S(O)—, —S(O)₂— and —N═; Z is a memberselected from the group consisting of a bond, —N═, —O—, —S—, —N(R¹⁷)—and —C(R⁷)═, with the proviso that X and Z are not both a bond; L is amember selected from the group consisting of a bond,C(O)—(C₁-C₈)alkylene, (C₁-C₈)alkylene and (C₂-C₈)heteroalkylene; Q is amember selected from the group consisting of a bond, (C₁-C₈)alkylene,(C₂-C₈)heteroalkylene, —C(O)—, —OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO—and —CH₂SO₂—; optionally L and Q can be linked together to form a 5- or6-membered heterocyclic group having from 1 to 3 heteroatoms; R¹ and R²are members independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and heteroaryl, or optionally arecombined to form a 3 to 8-membered ring having from 0 to 2 heteroatomsas ring vertices; optionally R² and L can be linked together to form a5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms; R³is a member selected from the group consisting of hydroxy,(C₁-C8)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, amidino,guanidino, ureido, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹; R⁴ is amember selected from the group consisting of (C₁-C₂₀)alkyl,(C₂-C₂₀)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkyl andaryl(C₂-C₆)heteroalkyl; R⁵ and R⁶ are each members independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally R⁵ and R⁶ arecombined to form a 3- to 7-membered ring; R⁷ and R⁸ are each membersindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, each R⁹, R¹⁰ and R¹¹ isindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; Y¹ and Y² are each members independentlyselected from the group consisting of —C(R¹²)═, —N═, —O—, —S— and—N(R¹³)—; Y³ is a member selected from the group consisting of N and Cwherein the carbon atom shares a double bond with either Z or Y⁴; and Y⁴is a member selected from the group consisting of —N(R¹⁴)—, —C(R¹⁴)═,—N═ and —N(R¹⁴)—C(R¹⁵)(R¹⁶)—, wherein each R¹² is a member independentlyselected from the group consisting of H, halogen, hydroxy, amino,alkylamino, dialkylamino, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryland aryl, or optionally when Y¹ and Y² are both —C(R¹²)═ the two R¹²groups can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; oroptionally when Y¹ is —C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² andR⁵ can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R¹³ isa member selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; R¹⁴ is a member selected from the groupconsisting of (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl,aryl(C₂-C₈)heteroalkyl, heteroaryl(C₁-C₈)alkyl,heteroaryl(C₂-C₈)heteroalkyl, heteroaryl and aryl; R¹⁵ and R¹⁶ are eachmembers independently selected from the group consisting of H,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; and R¹⁷ is a member selected fromthe group consisting of H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl,aryl, heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl,aryl(C₁-C₈)alkyl and aryl(C₂-C₈)heteroalkyl, or optionally when Y² is—C(R¹²)═ or —N(R¹³)—, R¹⁷ can be combined with R¹² or R¹³ to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; with the proviso that whenthe Y³-containing ring system is a quinazolinone or quinolinone ringsystem, and R⁴—Q— is substituted or unsubstituted (C₅-C₁₅)alkyl, thenR³—L— is other than substituted or unsubstituted (C₂-C₈)alkylene or asubstituted or unsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″,wherein R′ and R″ are independently selected from the group consistingof hydrogen and (C₁-C₈)alkyl, or optionally are combined with thenitrogen atom to which each is attached to form a 5-, 6- or 7-memberedring.
 2. A compound of claim 1, wherein Y⁴ is —N(R¹⁴)— wherein R¹⁴ isselected from the group consisting of aryl and heteroaryl.
 3. A compoundof claim 1, wherein X is —C(O)—
 4. A compound of claim 1, wherein Z is—N═.
 5. A compound of claim 1, wherein Y¹ and Y² are each —C(R¹²)═wherein the two R¹² groups are combined to form a fused 6-membered arylor heteroaryl ring.
 6. A compound of claim 1, wherein X is —C(O)—; Z is—N═; Y³ is C; and Y¹ and Y² are each —C(R²)═.
 7. A compound of claim 6,wherein the two R¹² groups are combined to form a fused 6-memberedsubstituted or unsubstituted aryl or heteroaryl ring.
 8. A compound ofclaim 6, wherein Y⁴ is —N(R¹⁴)—.
 9. A compound of claim 6, wherein Y⁴ is—C(R¹⁴)═.
 10. A compound of claim 7, wherein Y⁴ is —N(R¹⁴)—.
 11. Acompound of claim 7, wherein Y⁴ is —C(R¹⁴)═.
 12. A compound of claim 1,wherein L is (C₁-C₈)alkylene.
 13. A compound of claim 1, wherein Q is—C(O)—.
 14. A compound of claim 1, wherein R⁴ is selected from the groupconsisting of (C₅-C₁₅)alkyl, substituted or unsubstituted phenyl andbiphenyl.
 15. A compound of claim 1, wherein R³is selected from thegroup consisting of (C₁-C₈)alkoxy, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, (C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl,(C₁-C₈)acylamino, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹.
 16. Acompound of claim 1, wherein R¹ and R² are independently selected fromthe group consisting of H and (C₁-C₄)alkyl.
 17. A compound of claim 1,wherein Y³ is C and the carbon atom shares a double bond with Z.
 18. Acompound of claim 1, wherein X is —C(R⁵)(R⁶)—; Y⁴ is —N(R¹⁴)—, whereinR¹⁴is substituted or unsubstituted aryl or heteroaryl; Y³ is C; Z is—N═; and Y¹ and Y² are each —C(R¹²)═.
 19. A compound of claim 18,wherein X is —CH₂— and the R¹² groups are combined to form a substitutedor unsubstituted aryl or heteroaryl ring.
 20. A compound of claim 1,wherein X is —C(R⁵)═; Y⁴ is —C(R¹⁴)═, wherein R¹⁴is substituted orunsubstituted aryl or heteroaryl; Y³ is C; Z is —N═; and Y¹ and Y² areeach —C(R²)═.
 21. A compound of claim 20, wherein R¹ is H.
 22. Acompound of claim 1, wherein X is a bond; Y⁴ is —N(R¹⁴)—, wherein R¹⁴ issubstituted or unsubstituted aryl or heteroaryl; Y³ is C; Z is —N═; andY¹ and Y² are each —C(R¹²)═.
 23. A compound of claim 22, wherein the R¹²groups are combined to form a substituted or unsubstituted aryl orheteroaryl ring.
 24. A compound of claim 22, wherein R¹ is H.
 25. Acompound of claim 1, wherein X is —C(R⁵)═; Y⁴ is —C(R¹⁴)═, wherein R¹⁴is substituted or unsubstituted aryl or heteroaryl; Y³ is C; Z is—C(R⁷)═; and Y¹ and Y² are each —C(R¹²)═.
 26. A compound of claim 25,wherein R⁵ and R¹² are combined to form a 5- or 6-membered substitutedor unsubstituted aryl or heteroaryl ring.
 27. A compound of claim 25,wherein R¹ is H.
 28. A compound of claim 1, wherein X is a bond; Z is—N═ or —N(R¹⁷)—; Y⁴ is —C(R¹⁴)═, wherein R¹⁴ is substituted orunsubstituted aryl or heteroaryl; Y¹ is selected from the groupconsisting of —O—, —S— and —N(R³)—; and Y² is —C(R¹²)═.
 29. A compoundof claim 28, wherein Y¹ is —O— and Z is —N═.
 30. A compound of claim 28,wherein Y¹ is —S— and Z is —N═.
 31. A compound of claim 28, wherein Y¹is —N(R¹³)— and Z is —N═.
 32. A compound of claim 1, wherein X is —SO₂—;Y⁴ is —N(R¹⁴)═, wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; Y³is C; Z is —N═ or —C(R⁷)═; and Y¹ and Y² are each—C(R¹²)═.
 33. A compound of claim 32, wherein R¹ is H.
 34. A compound ofclaim 1, wherein X is a bond; Z is —O—, —S— or —N(R¹⁷)—; Y¹ is —N═ or—N(R³)—; Y² is —C(R¹²)═; and Y⁴ is —C(R¹⁴)═ wherein R¹⁴ is substitutedor unsubstituted aryl or heteroaryl.
 35. A compound of claim 34, whereinY¹ is —N═ and Z is —O—.
 36. A compound of claim 34, wherein Y¹ is —N═and Z is —S—.
 37. A compound of claim 34, wherein Z is —N(R¹⁷)—.
 38. Acompound of claim 34, wherein R¹ is H.
 39. A compound of claim 1,wherein X is a bond; Y¹ is —N(R 3)— or ═N—; Y² is —C(R¹²)═; Y³ is C; Y⁴is —C(R¹⁴)═ wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; and Z is —N(R¹⁷)— or ═N—, with the proviso that Y¹ and Z arenot both ═N—.
 40. A compound of claim 1, wherein X is a bond; Y¹ and Y²are each independently —C(R¹²)═; Y³ is C; Y⁴ is —C(R¹⁴)═ wherein R¹⁴ issubstituted or unsubstituted aryl or heteroaryl; and Z is —N(R¹⁷)—, O orS.
 41. A compound of claim 40, wherein the two R¹² groups are combinedto form a fused 5- or 6-membered substituted or unsubstituted aryl orheteroaryl ring.
 42. A compound of claim 1, wherein X is —C(O)—; Y¹ is—N(R¹³)—; Y² is —N═; Y³ is C; Y⁴ is —N(R¹⁴)— wherein R¹⁴ is substitutedor unsubstituted aryl or heteroaryl; and Z is a bond.
 43. A compound ofclaim 42, wherein R¹ is H.
 44. A compound of claim 1, wherein X is—C(O)—; Z is —N(R¹⁷)— wherein R¹⁷ is substituted or unsubstituted arylor heteroaryl; Y¹ and Y² are each independently —C(R¹²)═; Y³ is C; andY⁴ is —N═.
 45. A compound of claim 44, wherein R¹ is H.
 46. A compoundof claim 1, wherein X and Z are —N═, Y¹ and Y² are each independently—C(R¹²)═; Y³ is C; and Y⁴ is —C(R¹⁴ )═ wherein R¹⁴ is a substituted orunsubstituted aryl or heteroaryl group.
 47. A compound of claim 46,wherein R¹ is H.
 48. A compound of claim 1, wherein X is —C(O)—; Y⁴ is—N(R¹⁴)—C(R⁵)(R⁶)—; wherein R¹⁴ is substituted or unsubstituted aryl orheteroaryl; Y¹ and Y² are each independently —C(R¹²)═; Y³ is C; and Z is—N═.
 49. A compound of claim 48, wherein R¹ is H.
 50. A compound ofclaim 1, wherein the Y³-containing ring system is selected from thegroup consisting of quinoline, quinazoline, naphthalene, quinolinone,quinazolinone, triazolinone, pyrimidin-4-one, benzimidazole, thiazole,imidazole, pyridine, pyrazine and benzodiazepine.
 51. A compound ofclaim 1, having the formula (III):

wherein A⁴is C or N; X is —CO—, —CH₂— or a bond; R¹ and R² are eachmembers independently selected from the group consisting of H and(C₁-C₄)alkyl; R¹⁴ is a substituted or unsubstituted member selected fromthe group consisting of phenyl, pyridyl, thiazolyl, thienyl andpyrimidinyl; Q is —CO—; L is (C₁-C₈)alkylene; the subscript n is aninteger of from 0 to 4; and each R_(a) is independently selected fromthe group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.
 52. A compound of claim 51, wherein X is —C(O)—.53. A compound of claim 51, wherein X is —CH₂—.
 54. A compound of claim51, wherein X is a bond.
 55. A compound of claim 51, wherein R⁴ issubstituted or unsubstituted benzyl, wherein said substituents areselected from the group consisting of halogen, halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, cyano, nitro, and phenyl.
 56. A compound of claim 51,wherein R¹⁴ is selected from the group consisting of substituted phenyl,substituted pyridyl, substituted thiazolyl and substituted thienyl,wherein the substituents are selected from the group consisting ofcyano, halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, CONH₂,methylenedioxy and ethylenedioxy.
 57. A compound of claim 51, whereinR¹⁴ is substituted phenyl, wherein the substituents are selected fromthe group consisting of cyano, halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, CONH₂, methylenedioxy and ethylenedioxy.
 58. Acompound of claim 51, wherein R⁴ is substituted or unsubstituted benzyl,wherein said substituents are selected from the group consisting ofhalogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano, nitro and phenyl,and R¹⁴ is substituted phenyl, wherein the substituents are selectedfrom the group consisting of cyano, halogen, (C₁-C₈)alkoxy,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, CONH₂, methylenedioxy andethylenedioxy.
 59. A compound of claim 5 1, wherein R¹ is selected fromthe group consisting of methyl, ethyl and propyl, and R² is hydrogen.60. A compound of claim 5 1, wherein R¹ and R² are each methyl.
 61. Acompound of claim 5 1, wherein R³ is selected from the group consistingof (C₁-C₈)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl and heteroaryl.
 62. A compoundof claim 5 1, wherein R³ is selected from the group consisting ofsubstituted or unsubstituted pyridyl and substituted or unsubstitutedimidazolyl.
 63. A compound of claim 5 1, wherein L is (C₁-C₄)alkylene.64. A compound of claim 51, wherein X is —CO—; R¹ and R² are eachindependently selected from the group consisting of H, methyl and ethyl;R¹⁴ is phenyl; L is methylene, ethylene or propylene, R³ is selectedfrom the group consisting of substituted or unsubstituted pyridyl andsubstituted or unsubstituted imidazolyl; R⁴ is substituted orunsubstituted benzyl, wherein said substituents are selected from thegroup consisting of halogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano,nitro, and phenyl; and each R_(a) is selected from the group consistingof halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —NR″C(O)R′, —NR′—C(O)NR″R′″, perfluoro(C₁-C₄)alkoxy,and perfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.
 65. A compound of claim 51, wherein said compoundis selected from the group consisting of:


66. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or excipient and a compound having the formula (I):

wherein X is a member selected from the group consisting of a bond,—C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═, —S(O)—, —S(O)₂— and —N═; Z is a memberselected from the group consisting of a bond, —N═, —O—, —S—, —N(R¹⁷)—and —C(R⁷)═, with the proviso that X and Z are not both a bond; L is amember selected from the group consisting of a bond,C(O)—(C₁-C₈)alkylene, (C₁-C₈)alkylene and (C₂-C₈)heteroalkylene; Q is amember selected from the group consisting of a bond, (C₁-C₈)alkylene,(C₂-C₈)heteroalkylene, —C(O)—, —OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO—and —CH₂SO₂—; optionally L and Q can be linked together to form a 5- or6-membered heterocyclic group having from 1 to 3 heteroatoms; R¹ and R²are members independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and heteroaryl, or optionally arecombined to form a 3 to 8-membered ring having from 0 to 2 heteroatomsas ring vertices; optionally R² and L can be linked together to form a5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms; R³is a member selected from the group consisting of hydroxy,(C₁-C₈)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, amidino,guanidino, ureido, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹; R⁴ is amember selected from the group consisting of (C₁-C₂₀)alkyl,(C₂-C₂₀)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkyl andaryl(C₂-C₆)heteroalkyl; R⁵ and R⁶ are each members independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally R⁵ and R⁶ arecombined to form a 3- to 7-membered ring; R⁷ and R⁸ are each membersindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, each R⁹, R¹⁰ and R¹¹ isindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; Y¹ and Y² are each members independentlyselected from the group consisting of —C(R¹²)═, —N═, —O—, —S— and—N(R¹³)—; Y³ is a member selected from the group consisting of N and Cwherein the carbon atom shares a double bond with either Z or Y⁴; and Y⁴is a member selected from the group consisting of —N(R¹⁴)—, —C(R¹⁴)═,—N═ and —N(R¹⁴)—C(R¹⁵)(R¹⁶)—, wherein each R¹² is a member independentlyselected from the group consisting of H, halogen, hydroxy, amino,alkylamino, dialkylamino, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryland aryl, or optionally when Y¹ and Y² are both —C(R¹²)═ the two R¹²groups can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; oroptionally when Y¹ is —C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² andR⁵ can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R¹³ isa member selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; R¹⁴ is a member selected from the groupconsisting of (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl,aryl(C₂-C₈)heteroalkyl, heteroaryl(C₁-C₈)alkyl,heteroaryl(C₂-C₈)heteroalkyl, heteroaryl and aryl; R¹⁵ and R¹⁶ are eachmembers independently selected from the group consisting of H,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; and R¹⁷ is a member selected fromthe group consisting of H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl,aryl, heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl,aryl(C₁-C₈)alkyl and aryl(C₂-C₈)heteroalkyl, or optionally when Y² is—C(R¹²)═ or —N(R¹³)—, R¹⁷ can be combined with R¹² or R¹³ to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; with the proviso that whenthe Y³-containing ring system is a quinazolinone or quinolinone ringsystem, and R⁴—Q— is substituted or unsubstituted (C₅-C₁₅)alkyl, thenR³—L— is other than substituted or unsubstituted (C₂-C₈)alkylene or asubstituted or unsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″,wherein R′ and R″ are independently selected from the group consistingof hydrogen and (C₁-C₈)alkyl, or optionally are combined with thenitrogen atom to which each is attached to form a 5-, 6- or 7-memberedring.
 67. A composition of claim 66, wherein Y⁴ is —N(R¹⁴)— wherein R¹⁴is selected from the group consisting of aryl and heteroaryl.
 68. Acomposition of claim 66, wherein X is —C(O)—.
 69. A composition of claim66, wherein Z is —N═.
 70. A composition of claim 66, wherein Y¹ and Y²are each —C(R 2)═ wherein the two R¹² groups are combined to form afused 6-membered aryl or heteroaryl ring.
 71. A composition of claim 66,wherein X is —C(O)—; Z is —N═; Y³ is C; and Y¹ and Y² are each —C(R¹²)═wherein the two R¹² groups are combined to form a fused 6-memberedsubstituted or unsubstituted aryl or heteroaryl ring.
 72. A compositionof claim 66, wherein L is (C₁-C₈)alkylene.
 73. A composition of claim66, wherein Q is —C(O)—.
 74. A composition of claim 66, wherein R⁴ isselected from the group consisting of (C₅-C₁₅)alkyl, substituted orunsubstituted phenyl and biphenyl.
 75. A composition of claim 66,wherein R³ is selected from the group consisting of (C₁-C₈)alkoxy,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, (C₂-C₈)heteroalkyl,(C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, cyano, heteroaryl, —CONR⁹R¹⁰ and—CO₂R¹¹.
 76. A composition of claim 66, wherein R¹ and R² areindependently selected from the group consisting of H and (C₁-C₄)alkyl.77. A composition of claim 66, wherein Y³ is C and the carbon atomshares a double bond with Z.
 78. A composition of claim 66, wherein theY³-containing ring system is selected from the group consisting ofquinoline, quinazoline, naphthalene, quinolinone, quinazolinone,triazolinone, pyrimidin-4-one, benzimidazole, thiazole, imidazole,pyridine, pyrazine and benzodiazepine.
 79. A composition of claim 66,wherein the compound has the formula (III):

wherein A⁴is C or N; X is —CO—, —CH₂— or a bond; R¹ and R² are eachmembers independently selected from the group consisting of H and(C₁-C₄)alkyl; R¹⁴ is a substituted or unsubstituted member selected fromthe group consisting of phenyl, pyridyl, thiazolyl, thienyl andpyrimidinyl; Q is —CO—; L is (C₁-C₈)alkylene; the subscript n is aninteger of from 0 to 4; and each R_(a) is independently selected fromthe group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR″C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,unsubstituted aryl, unsubstituted heteroaryl, (unsubstitutedaryl)-(C₁-C₄)alkyl, and (unsubstituted aryl)oxy-(C₁-C₄)alkyl.
 80. Acomposition in accordance with claim 79, wherein X is —C(O)—.
 81. Acomposition in accordance with claim 79, wherein X is —CH₂—.
 82. Acomposition in accordance with claim 79, wherein X is a bond.
 83. Acomposition in accordance with claim 79, wherein R⁴ is substituted orunsubstituted benzyl, wherein said substituents are selected from thegroup consisting of halogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano,nitro, and phenyl.
 84. A composition in accordance with claim 79,wherein R¹⁴ is selected from the group consisting of substituted phenyl,substituted pyridyl, substituted thiazolyl and substituted thienyl,wherein the substituents are selected from the group consisting ofcyano, halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, CONH₂,methylenedioxy and ethylenedioxy.
 85. A composition in accordance withclaim 79, wherein R¹ is selected from the group consisting of methyl,ethyl and propyl, and R² is.
 86. A composition in accordance with claim79, wherein R¹ and R² are each methyl.
 87. A composition in accordancewith claim 79, wherein R³ is selected from the group consisting ofsubstituted or unsubstituted pyridyl and substituted or unsubstitutedimidazolyl.
 88. A composition in accordance with claim 79, wherein L is(C₁-C₄)alkylene.
 89. A composition in accordance with claim 79, whereinX is —CO—; R¹ and R² are each independently selected from the groupconsisting of, methyl and ethyl; R¹⁴ is selected from the groupconsisting of substituted or unsubstituted phenyl; L is methylene,ethylene or propylene, R³ is selected from the group consisting ofsubstituted or unsubstituted pyridyl and substituted or unsubstitutedimidazolyl; R⁴ is substituted or unsubstituted benzyl, wherein saidsubstituents are selected from the group consisting of halogen,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano, nitro, and phenyl; and eachR_(a) is selected from the group consisting of halogen, —OR′, —OC(O)R′,—NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —NR″C(O)R′,—NR′—C(O)NR″R′″, perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl,wherein R′, R″ and R′″ are each independently selected from the groupconsisting of, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, unsubstituted aryl,unsubstituted heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and(unsubstituted aryl)oxy-(C₁-C₄)alkyl.
 90. The composition of claim 79,wherein said compound is:


91. A method of treating an inflammatory or immune condition or diseasein a subject, said method comprising administering to a subject in needof such treatment a therapeutically effective amount of a compoundhaving the formula (I):

wherein X is a member selected from the group consisting of a bond,—C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═, —S(O)—, —S(O)₂— and —N═; Z is a memberselected from the group consisting of a bond, —N═, —O—, —S—, —N(R¹⁷)—and —C(R⁷)═, with the proviso that X and Z are not both a bond; L is amember selected from the group consisting of a bond,C(O)—(C₁-C₈)alkylene, (C₁-C₈)alkylene and (C₂-C₈)heteroalkylene; Q is amember selected from the group consisting of a bond, (C₁-C₈)alkylene,(C₂-C₈)heteroalkylene, —C(O)—, —OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO—and —CH₂SO₂—; optionally L and Q can be linked together to form a 5- or6-membered heterocyclic group having from 1 to 3 heteroatoms; R¹ and R²are members independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and heteroaryl, or optionally arecombined to form a 3 to 8-membered ring having from 0 to 2 heteroatomsas ring vertices; optionally R² and L can be linked together to form a5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms; R³is a member selected from the group consisting of hydroxy,(C₁-C₈)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, amidino,guanidino, ureido, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹; R⁴ is amember selected from the group consisting of (C₁-C₂₀)alkyl,(C₂-C₂₀)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkyl andaryl(C₂-C₆)heteroalkyl; R⁵ and R⁶ are each members independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally R⁵ and R⁶ arecombined to form a 3- to 7-membered ring; R⁷ and R⁸ are each membersindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, each R⁹, R¹⁰ and R¹¹ isindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; Y¹ and Y² are each members independentlyselected from the group consisting of —C(R¹²)═, —N═, —O—, —S— and—N(R¹³)—; Y³ is a member selected from the group consisting of N and Cwherein the carbon atom shares a double bond with either Z or Y⁴; and Y⁴is a member selected from the group consisting of —N(R¹⁴)—, —C(R¹⁴)═,—N═ and —N(R¹⁴)—C(R¹⁵)(R¹⁶)—, wherein each R¹² is a member independentlyselected from the group consisting of H, halogen, hydroxy, amino,alkylamino, dialkylamino, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryland aryl, or optionally when Y¹ and Y² are both —C(R¹²)═ the two R¹²groups can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; oroptionally when Y¹ is —C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² andR⁵ can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R¹³ isa member selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; R¹⁴ is a member selected from the groupconsisting of (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl,aryl(C₂-C₈)heteroalkyl, heteroaryl(C₁-C₈)alkyl,heteroaryl(C₂-C₈)heteroalkyl, heteroaryl and aryl; R¹⁵ and R¹⁶ are eachmembers independently selected from the group consisting of H,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; and R¹⁷ is a member selected fromthe group consisting of H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl,aryl, heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl,aryl(C₁-C₈)alkyl and aryl(C₂-C₈)heteroalkyl, or optionally when Y² is—C(R¹²)═ or —N(R¹³)—, R¹⁷ can be combined with R¹² or R¹³ to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; with the proviso that whenthe Y³-containing ring system is a quinazolinone or quinolinone ringsystem, and R⁴—Q— is substituted or unsubstituted (C₅-C₁₅)alkyl, thenR³—L— is other than substituted or unsubstituted (C₂-C₈)alkylene or asubstituted or unsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″,wherein R′ and R″ are independently selected from the group consistingof hydrogen and (C₁-C₈)alkyl, or optionally are combined with thenitrogen atom to which each is attached to form a 5-, 6- or 7-memberedring.
 92. The method of claim 91, wherein said compound is administeredorally, parenterally or topically.
 93. The method of claim 91, whereinsaid compound modulates CXCR3.
 94. The method of claim 91, wherein saidcompound is a CXCR3 antagonist.
 95. The method of claim 91, wherein saidinflammatory or immune condition or disease is selected from the groupconsisting of neurodegenerative diseases, multiple sclerosis, systemiclupus erythematosus, rheumatoid arthritis, atherosclerosis,encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,psoriasis, eczema, uticaria, type I diabetes, asthma, conjunctivitis,otitis, allergic rhinitis, chronic obstructive pulmonary disease,sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis,Crohn's disease, Behcet's syndrome, gout, cancer, viral infections,bacterial infections, organ transplant conditions and skin transplantconditions.
 96. The method of claim 91, wherein said compound isadministered in combination with a second therapeutic agent, whereinsaid second therapeutic agent is useful for treating or preventingneurodegenerative diseases, multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis, atherosclerosis, encephalitis,meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis,eczema, uticaria, type I diabetes, asthma, conjunctivitis, otitis,allergic rhinitis, chronic obstructive pulmonary disease, sinusitis,dermatitis, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, Behcet's syndrome, gout, cancer, viral infections, bacterialinfections, organ transplant conditions or skin transplant conditions.97. A method of treating a CXCR3-mediated condition or disease in asubject, said method comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of a compound havingthe formula (I):

wherein X is a member selected from the group consisting of a bond,—C(O)—, —C(R⁵)(R⁶)—, —C(R⁵)═, —S(O)—, —S(O)₂— and —N═; Z is a memberselected from the group consisting of a bond, —N═, —O—, —S—, —N(R¹⁷)—and —C(R⁷)═, with the proviso that X and Z are not both a bond; L is amember selected from the group consisting of a bond,C(O)—(C₁-C₈)alkylene, (C₁-C₈)alkylene and (C₂-C₈)heteroalkylene; Q is amember selected from the group consisting of a bond, (C₁-C₈)alkylene,(C₂-C₈)heteroalkylene, —C(O)—, —OC(O)—, —N(R⁸)C(O)—, —CH₂CO—, —CH₂SO—and —CH₂SO₂—; optionally L and Q can be linked together to form a 5- or6-membered heterocyclic group having from 1 to 3 heteroatoms; R¹ and R²are members independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and heteroaryl, or optionally arecombined to form a 3 to 8-membered ring having from 0 to 2 heteroatomsas ring vertices; optionally R² and L can be linked together to form a5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms; R³is a member selected from the group consisting of hydroxy,(C₁-C₈)alkoxy, amino, (C₁-C₈)alkylamino, di(C₁-C₈)alkylamino,(C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl, (C₁-C₈)acylamino, amidino,guanidino, ureido, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹; R⁴ is amember selected from the group consisting of (C₁-C₂₀)alkyl,(C₂-C₂₀)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₆)heteroalkyl, aryl(C₁-C₆)alkyl andaryl(C₂-C₆)heteroalkyl; R⁵ and R⁶ are each members independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, or optionally R⁵ and R⁶ arecombined to form a 3- to 7-membered ring; R⁷ and R⁸ are each membersindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl and aryl, each R⁹, R¹⁰ and R¹¹ isindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; Y¹ and Y² are each members independentlyselected from the group consisting of-C(R¹²)═, —N═, —O—, —S— and—N(R³)—; Y³ is a member selected from the group consisting of N and Cwherein the carbon atom shares a double bond with either Z or Y⁴; and Y⁴is a member selected from the group consisting of —N(R¹⁴)—, —C(R¹⁴)═,—N═ and —N(R¹⁴)—C(R¹⁵)(R¹⁶)—, wherein each R¹² is a member independentlyselected from the group consisting of H, halogen, hydroxy, amino,alkylamino, dialkylamino, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryland aryl, or optionally when Y¹ and Y² are both —C(R¹²)═ the two R¹²groups can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; oroptionally when Y¹ is —C(R¹²)═ and X is —C(R⁵)═ or —C(R⁵)(R⁶)—, R¹² andR⁵ can be combined to form a substituted or unsubstituted 5- to6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R¹³ isa member selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, heteroaryl, aryl, heteroaryl(C₁-C₆)alkyl,heteroaryl(C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl andaryl(C₂-C₈)heteroalkyl; R¹⁴ is a member selected from the groupconsisting of (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl(C₁-C₈)alkyl,aryl(C₂-C₈)heteroalkyl, heteroaryl(C₁-C₈)alkyl,heteroaryl(C₂-C₈)heteroalkyl, heteroaryl and aryl; R¹⁵ and R¹⁶ are eachmembers independently selected from the group consisting of H,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; and R¹⁷ is a member selected fromthe group consisting of H, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, heteroaryl,aryl, heteroaryl(C₁-C₆)alkyl, heteroaryl(C₂-C₈)heteroalkyl,aryl(C₁-C₈)alkyl and aryl(C₂-C₈)heteroalkyl, or optionally when Y² is—C(R¹²)═ or —N(R¹³)—, R¹⁷ can be combined with R¹² or R¹³ to form asubstituted or unsubstituted 5- to 6-membered cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring; with the proviso that whenthe Y³-containing ring system is a quinazolinone or quinolinone ringsystem, and R⁴—Q— is substituted or unsubstituted (C₅-C₁₅)alkyl, thenR³—L— is other than substituted or unsubstituted (C₂-C₈)alkylene or asubstituted or unsubstituted (C₂-C₈)heteroalkylene attached to —NR′R″,wherein R′ and R″ are independently selected from the group consistingof hydrogen and (C₁-C₈)alkyl, or optionally are combined with thenitrogen atom to which each is attached to form a 5-, 6- or 7-memberedring.
 98. A method in accordance with claim 97, wherein Y⁴ is —N(R¹⁴)—wherein R¹⁴ is selected from the group consisting of aryl andheteroaryl.
 99. A method in accordance with claim 97, wherein X is—C(O)—.
 100. A method in accordance with claim 97, wherein Z is —N═.101. A method in accordance with claim 97, wherein Y¹ and Y² are each—C(R¹²)═, wherein the two R¹² groups are combined to form a fused6-membered aryl or heteroaryl ring.
 102. A method in accordance withclaim 97, wherein X is —C(O)—; Z is —N═; Y³ is C; and Y¹ and Y² are each—C(R¹²)═ wherein the two R¹² groups are combined to form a fused6-membered substituted or unsubstituted aryl or heteroaryl ring.
 103. Amethod in accordance with claim 97, wherein L is (C₁-C₈)alkylene.
 104. Amethod in accordance with claim 97, wherein Q is —C(O)—.
 105. A methodin accordance with claim 97, wherein R⁴ is selected from the groupconsisting of (C₅-C₁₅)alkyl, substituted or unsubstituted phenyl andbiphenyl.
 106. A method in accordance with claim 97, wherein R³ isselected from the group consisting of (C₁-C₈)alkoxy, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, (C₂-C₈)heteroalkyl, (C₃-C₉)heterocyclyl,(C₁-C₈)acylamino, cyano, heteroaryl, —CONR⁹R¹⁰ and —CO₂R¹¹.
 107. Amethod in accordance with claim 97, wherein R¹ and R² are independentlyselected from the group consisting of H and (C₁-C₄)alkyl.
 108. A methodin accordance with claim 97, wherein Y³ is C and the carbon atom sharesa double bond with Z.
 109. A method in accordance with claim 97, whereinthe Y³-containing ring system is selected from the group consisting ofquinoline, quinazoline, naphthalene, quinolinone, quinazolinone,triazolinone, pyrimidin-4-one, benzimidazole, thiazole, imidazole,pyridine, pyrazine and benzodiazepine.
 110. A method in accordance withclaim 97, wherein said compound has the formula (III):

wherein A⁴is C or N; X is —CO—, —CH₂— or a bond; R¹ and R² are eachmembers independently selected from the group consisting of H and(C₁-C₄)alkyl; R¹⁴ is a substituted or unsubstituted member selected fromthe group consisting of phenyl, pyridyl, thiazolyl, thienyl andpyrimidinyl; Q is —CO—; L is (C₁-C₈)alkylene; the subscript n is aninteger of from 0 to 4; and each R_(a) is independently selected fromthe group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.
 111. A method in accordance with claim 110,wherein X is —C(O)—.
 112. A method in accordance with claim 110, whereinX is —CH₂—.
 113. A method in accordance with claim 110, wherein X is abond.
 114. A method in accordance with claim 110, wherein R⁴ issubstituted or unsubstituted benzyl, wherein said substituents areselected from the group consisting of halogen, halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, cyano, nitro, and phenyl.
 115. A method in accordancewith claim 110, wherein R is selected from the group consisting ofsubstituted phenyl, substituted pyridyl, substituted thiazolyl andsubstituted thienyl, wherein the substituents are selected from thegroup consisting of cyano, halogen, (C₁-C₈)alkoxy, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, CONH₂, methylenedioxy and ethylenedioxy.
 116. Amethod in accordance with claim 110, wherein R¹ is selected from thegroup consisting of methyl, ethyl and propyl, and R² is hydrogen.
 117. Amethod in accordance with claim 110, wherein R¹ and R² are each methyl.118. A method in accordance with claim 110, wherein R³ is selected fromthe group consisting of substituted or unsubstituted pyridyl andsubstituted or unsubstituted imidazolyl.
 119. A method in accordancewith claim 110, wherein L is (C₁-C₄)alkylene.
 120. A method inaccordance with claim 110, wherein X is —CO—; R¹ and R² are eachindependently selected from the group consisting of H, methyl and ethyl;R¹⁴ is selected from the group consisting of substituted orunsubstituted phenyl; Q is —CO—; L is methylene, ethylene or propylene,R³ is selected from the group consisting of substituted or unsubstitutedpyridyl and substituted or unsubstituted imidazolyl; R⁴ is substitutedor unsubstituted benzyl, wherein said substituents are selected from thegroup consisting of halogen, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, cyano,nitro, and phenyl; and each R_(a) is selected from the group consistingof halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —NR″C(O)R′, —NR′-C(O)NR″R′″, perfluoro(C₁-C₄)alkoxy,and perfluoro(C₁-C₄)alkyl, wherein R′, R″ and R′″ are each independentlyselected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.
 121. The method of claim 110, wherein saidcompound is selected from the group consisting of:


122. A method in accordance with claim 97, wherein said CXCR3-mediatedcondition is selected from the group consisting of neurodegenerativediseases, multiple sclerosis, systemic lupus erythematosus, rheumatoidarthritis, atherosclerosis, encephalitis, meningitis, hepatitis,nephritis, sepsis, sarcoidosis, psoriasis, eczema, uticaria, type Idiabetes, asthma, conjunctivitis, otitis, allergic rhinitis, chronicobstructive pulmonary disease, sinusitis, dermatitis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, Behcet's syndrome, gout,cancer, viral infections, bacterial infections, organ transplantconditions and skin transplant conditions.
 123. The method of claim 97,wherein said compound modulates CXCR3.
 124. A method in accordance withclaim 110, wherein said compound is administered in combination with asecond therapeutic agent, wherein said second therapeutic agent isuseful for treating neurodegenerative diseases, multiple sclerosis,systemic lupus erythematosus, rheumatoid arthritis, atherosclerosis,encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,psoriasis, eczema, uticaria, type I diabetes, asthma, conjunctivitis,otitis, allergic rhinitis, chronic obstructive pulmonary disease,sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis,Crohn's disease, Behcet's syndrome, gout, cancer, viral infections,bacterial infections, organ transplant conditions or skin transplantconditions.
 125. A method in accordance with claim 124, wherein saidorgan transplant condition is a bone marrow transplant condition or asolid organ transplant condition.
 126. A method in accordance with claim125, wherein said solid organ transplant condition is a kidneytransplant condition, a liver transplant condition, a lung transplantcondition, a heart transplant condition or a pancreas transplantcondition.
 127. A method in accordance with claim 97, wherein saidCXCR3-mediated condition is restenosis.
 128. A method in accordance withclaim 97, wherein said CXCR3-mediated condition is selected from thegroup consisting of multiple sclerosis, rheumatoid arthritis and organtransplant conditions.
 129. A method in accordance with claim 110,wherein said compound is used in conjunction with another therapeuticagent selected from the group consisting of Remicade®, Enbrel®, a COX-2inhibitor, a glucocorticoid, an immunosuppressant, methotrexate,predisolone, azathioprine, cyclophosphamide, tacrolimus, mycophenolate,hydroxychloroquine, sulfasalazine, cyclosporine A, D-penicillamine, agold compound, an antilymphocyte or antithymocyte globulin, betaseron,avonex and copaxone.
 130. A method in accordance with claim 110, whereinsaid CXCR3-mediated condition is an organ transplant condition and saidcompound is used alone or in combination with a second therapeutic agentselected from the group consisting of cyclosporine A, FK-506, rapamycin,mycophenolate, prednisolone, azathioprene, cyclophosphamide and anantilymphocyte globulin.
 131. A method in accordance with claim 110,wherein said CXCR3-mediated condition is rheumatoid arthritis and saidcompound is used alone or in combination with a second therapeutic agentselected from the group consisting of methotrexate, sulfasalazine,hydroxychloroquine, cyclosporine A, D-penicillamine, Remicade®, Enbrel®,auranofin and aurothioglucose.
 132. A method in accordance with claim110, wherein said CXCR3-mediated condition is multiple sclerosis andsaid compound is used alone or in combination with a second therapeuticagent selected from the group consisting of betaseron, avonex,azathioprene, capoxone, prednisolone and cyclophosphamide.
 133. Themethod of claim 110, wherein said subject is a human.
 134. A method forthe modulation of CXCR3 function in a cell, comprising contacting saidcell with a compound of claim
 1. 135. A method for the modulation ofCXCR3 function, comprising contacting a CXCR3 protein with a compound ofclaim 1.